TSUNODA Ikuo

    Department of Medicine Professor/Senior Staff
Last Updated :2024/03/25

Researcher Information

Degree

  • MD(1990/03 Tohoku University School of Medicine)
  • PhD(1994/03 Tohoku University)

URL

Research funding number

  • 00261529

ORCID ID

Researcher ID

  • B-4722-2008

J-Global ID

Profile

  • Our research is aimed at elucidating the pathogenesis of autoimmune disorders and virus infections in the central nervous system (CNS), using autoimmune and viral models for multiple sclerosis (MS): experimental autoimmune (allergic) encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus (TMEV) infection in mice. We have studied both host immune responses and pathogens (viruses), in vivo and in vitro, using immunological, virological, and neuropathological methods. Although axonal degeneration has been described in MS, it was believed to occur only secondarily to demyelination. We have demonstrated that 1) axonal damage precedes demyelination in TMEV infection (Inside-Out model) and 2) axonal degeneration plays a detrimental role in EAE, while it plays a beneficial role in TMEV infection, and 3) axonal degeneration recruits inflammatory cells to sites of Wallerian degeneration. We hypothesize that axonal degeneration can be a self-destructive defense mechanism that limits the spread of neurotropic viruses. We have also conducted studies on the roles of autoreactive CD8+ cytotoxic T cells (CTL) and natural killer T (NKT) cells in TMEV infection and established a mouse model for primary progressive (PP)- and secondary progressive (SP)-MS. This established model system will be used to elucidate the roles for cytokines, natural antibody, and apoptosis in lymphoid organs in deciphering how these factors interact and contribute to switching a disease course of autoimmune diseases from relapsing-remitting to a progressive type. Recently, we have established a viral model for myocarditis in mice.

Research Interests

  • Multiple Sclerosis   Bioinformatics   Neuroimmunology   Neurovirology   Virology   

Research Areas

  • Life sciences / Immunology / Autoimmunity
  • Life sciences / Laboratory animal science / EAE
  • Life sciences / Virology / Multiple sclerosis

Academic & Professional Experience

  • 2016/04 - Today  Kindai UniversityFaculty of Medicine Dept MicrobiolProfessor
  • 2016/04 - Today  Kindai University Faculty of MedicineDepartment of MicrobiologyProfessor and Chair
  • 2015/07 - 2016/03  Louisiana State University Health Sciences CenterDepartment of NeurologyAdjunct Associate Professor
  • 2015/07 - 2016/03  Louisiana State University Health Sciences CenterDepartment of Microbiology and ImmunologyAssociate Professor
  • 2009/07 - 2015/06  Louisiana State University Health Sciences CenterDepartment of Microbiology and ImmunologyAssistant Professor
  • 2008/01 - 2009/06  University of Utah School of MedicineDepartment of NeurologyAdjunct Assistant Professor
  • 2007/10 - 2009/06  University of Utah School of MedicineDepartment of Pathology, Division of Cell Biology & ImmunologyAssistant Professor
  • 2005/03 - 2007/09  University of Utah School of MedicineDepartment of NeurologyAssistant Professor
  • 2002/07 - 2005/02  University of Utah School of MedicineDepartment of NeurologyInstructor
  • 1999/01 - 2002/06  University of Utah School of MedicineDepartment of NeurologyResearch Associate
  • 1995/01 - 1998/12  University of Utah School of MedicineDepartment of NeurologyPostdoctoral Fellow
  • 1994/04 - 1994/12  Tohoku University School of MedicineDepartment of Neurological SciencesResearch Associate

Education

  • 1990/04 - 1994/03  Tohoku University  Graduate School of Medicine  Neuropathology
  • 1984/04 - 1990/03  Tohoku University  School of Medicine

Association Memberships

  • Japanese Society of Pathophysiology   THE JAPANESE SOCIETY FOR VIROLOGY   American Society for Microbiology (ASM)   American Association of Immunologists (AAI)   American Society for Virology (ASV)   Japanese Society for Neuroinfectious Diseases   Japanese Society for Neuroimmunology   

Published Papers

  • Ijaz Ahmad; Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Sundar Khadka; Felicity N. E. Gavins; Hiroki Tanaka; Motoko Y. Kimura; Ikuo Tsunoda
    International Journal of Molecular Sciences 2024/03
  • Kota Moriguchi; Yumina Nakamura; Ah-Mee Park; Fumitaka Sato; Motoi Kuwahara; Sundar Khadka; Seiichi Omura; Ijaz Ahmad; Susumu Kusunoki; Ikuo Tsunoda
    International Journal of Molecular Sciences MDPI AG 24 (16) 12937 - 12937 2023/08 [Refereed]
     
    Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain–Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35–55, MOG92–106, or myelin proteolipid protein (PLP)139–151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler’s murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139–151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies.
  • Cong Thanh NGUYEN; Yasushi Ito; Ikuo Tsunoda
    Medical Science Digest 北隆館 49 (6) 388 - 390 2023/06 [Invited]
     
    新型コロナウイルス感染症(COVID-19)に見られる血栓症の原因のひとつとして血管内皮細胞の機能不全が示唆されている。 ニコチンアデニンジヌクレオチド(NAD)は,細胞のエネルギー代謝に重要な因子であるが,NAD 代謝異常が内皮細胞機能障害に寄与する可能性がある。一方,感染時に誘導される炎症により組織に低酸素応答 が誘導され,これがNAD 合成に寄与している可能性がある。本論文では,COVID-19 の急性肺炎症モデルとタイラーウイルス感染による慢性中枢神経炎症モデルを用い,NAD 分解酵素CD38 と低酸素誘導分子HIF が内皮細胞障害において果たしうる役割について解説する。
  • Sundar Khadka; Seiichi Omura; Fumitaka Sato; Ikuo Tsunoda
    International Journal of Molecular Sciences MDPI AG 24 (3) 2818 - 2818 2023/02 [Refereed]
     
    Alterations in the gut microbiota, “dysbiosis,” have been reported in autoimmune diseases, including multiple sclerosis (MS), and their animal models. Although the animal models were induced by injections of autoantigens with adjuvants, including complete Freund’s adjuvant (CFA) and pertussis toxin (PT), the effects of adjuvant injections on the microbiota are largely unknown. We aimed to clarify whether adjuvant injections could affect the microbiota in the ileum and feces. Using 16S rRNA sequencing, we found decreased alpha diversities of the gut microbiota in mice injected with CFA and PT, compared with naïve mice. Overall, microbial profiles visualized by principal component analysis demonstrated dysbiosis in feces, but not in the ileum, of adjuvant-injected mice, where the genera Lachnospiraceae NK4A136 group and Alistipes contributed to dysbiosis. When we compared the relative abundances of individual bacteria, we found changes in 16 bacterial genera in feces and seven genera in the ileum of adjuvant-injected mice, in which increased serum levels of antibody against mycobacteria (a component of CFA) and total IgG2c were correlated with the genus Facklamia. On the other hand, increased IgG1 and IgA concentrations were correlated with the genus Atopostipes. Therefore, adjuvant injections alone could alter the overall microbial profiles (i.e., microbiota) and individual bacterial abundances with altered antibody responses; dysbiosis in animal models could be partly due to adjuvant injections.
  • Myadagmaa Jaalkhorol; Oyunbileg Dulamsuren; Amarsaikhan Dashtseren; Enkh-Amgalan Byambajav; Nansalmaa Khaidav; Badrangui Bat-Orgil; Anar Bold; Enkhdulguun Amgalan; Anujin Chuluunbaatar; Ikuo Tsunoda
    Pathophysiology 30 (1) 15 - 26 2023/01 [Refereed]
     
    Mongolia is located at 45° north latitude in the center of the Asian continent, and about 80% of the territory is at 1000 m above sea level. Epidemiologically, multiple sclerosis (MS) has not been investigated in Mongolia, although there have been a few MS case reports. We investigated the characteristics of MS in Mongolia for the first time, focusing on the association between MS-related parameters and depression levels. We initiated cross-sectional analyses, using data from 27 MS patients aged 20 to 60 years in Ulaanbaatar, Mongolia. The patients completed a questionnaire on their lifestyles and clinical information. We classified the MS patients on the basis of disability levels using the expanded disability status scale (EDSS) scores: 11.1% mild disability and 88.9% moderate to severe disability (median EDSS score, 5.5). We also classified the patients on the basis of depression levels using the 9-item patient health questionnaire (PHQ-9) scores: 44.4% mild depression, 40.7% moderate depression, and 14.8% severe depression (mean PHQ-9’s score, 9.96 ± 5.05). We used multivariate logistical regression analyses to identify predictors of EDSS or PHQ-9 scores. Disability levels were associated with vision and balance problems. Depression levels were associated with corticosteroid treatment; no patients were treated with disease-modifying drugs (DMDs). The odds ratios for disease onset age and treatment duration were associated with EDSS scores. In conclusion, MS onset age and treatment duration were independent predicting factors influencing the level of disability. Appropriate DMD treatment would lower the disability and depression levels.
  • Noriomi Matsumura; Reona Shiro; Ikuo Tsunoda
    Cancer science 114 (4) 1218 - 1228 2023/01 [Refereed]
     
    Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies", particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. Since Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."
  • Seiichi Omura; Kazuaki Shimizu; Motoi Kuwahara; Miyuki Morikawa-Urase; Susumu Kusunoki; Ikuo Tsunoda
    Scientific Reports Springer Science and Business Media LLC 12 (1) 2022/12 [Refereed]
     
    Abstract Exploratory factor analysis (EFA) has been developed as a powerful statistical procedure in psychological research. EFA’s purpose is to identify the nature and number of latent constructs (= factors) underlying a set of observed variables. Since the research goal of EFA is to determine what causes the observed responses, EFA is ideal for hypothesis-based studies, such as identifying the number and nature of latent factors (e.g., cause, risk factors, etc.). However, the application of EFA in the biomedical field has been limited. Guillain–Barré syndrome (GBS) is peripheral neuropathy, in which the presence of antibodies to glycolipids has been associated with clinical signs. Although the precise mechanism for the generation of anti-glycolipid antibodies is unclear, we hypothesized that latent factors, such as distinct autoantigens and microbes, could induce different sets of anti-glycolipid antibodies in subsets of GBS patients. Using 55 glycolipid antibody titers from 100 GBS and 30 control sera obtained by glycoarray, we conducted EFA and extracted four factors related to neuroantigens and one potentially suppressive factor, each of which was composed of the distinct set of anti-glycolipid antibodies. The four groups of anti-glycolipid antibodies categorized by unsupervised EFA were consistent with experimental and clinical findings reported previously. Therefore, we proved that unsupervised EFA could be applied to biomedical data to extract latent factors. Applying EFA for other biomedical big data may elucidate latent factors of other diseases with unknown causes or suppressing/exacerbating factors, including COVID-19.
  • 神経免疫疾患のバリア破綻の病態と治療 バリア(腸管バリア、BBB)破綻を伴うCNS免疫性疾患における脳内の「菌の定着colonization」の注意点
    角田 郁生; 朴 雅美; 尾村 誠一; 堀田 芙美香; 城 玲央奈; Sundar Khadka; Ijaz Ahmad; 森口 幸太; 佐藤 文孝
    神経免疫学 (一社)日本神経免疫学会 27 (1) 79 - 79 0918-936X 2022/10
  • Ah-Mee Park; Ikuo Tsunoda
    Inflammation and Regeneration Springer Science and Business Media LLC 42 (1) 39 - 39 2022/09 [Refereed]
     
    Abstract Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since HP does not invade the central nervous system (CNS), it has been considered that systemic immunological changes induced by HP infection may play pathogenic roles in AD and PD. Here, we investigated the effects of HP infection on the CNS in vivo and in vitro. In the CNS, chronically HP-infected mice had microglial activation without HP colonization, although systemic immunological changes were not observed. This led us to explore the possibility that HP-derived outer membrane vesicles (HP-OMVs) could cause neuroinflammation. OMVs are small, spherical bilayer vesicles (20–500 nm) released into the extracellular space from the outer membrane of Gram-negative bacteria; OMVs contain lipopolysaccharide, proteins, peptidoglycan, DNA, and RNA. OMVs have also been shown to activate both innate and acquired immune cells in vitro, and to disrupt the tight junctions of the gastric epithelium (“leaky gut”) as well as cross the blood-brain barrier in vivo. Thus, in theory, OMVs can activate immune responses in the remote organs, including the lymphoid organs and CNS, if only OMVs enter the systemic circulation. From the exosome fraction of sera from HP-infected mice, we detected HP-specific DNA, suggesting the presence of HP-OMVs. We also found that microglia incubated with HP-OMVs in vitro increased the cell proliferation, inflammatory cytokine production, and migration. On the other hand, HP-OMVs suppressed the cell proliferation of neuroblastoma in vitro. Lastly, we found that AD model mice infected with HP had amyloid plaques adjacent to activated microglia and astrocytes in vivo. Based on the literature review and our experimental data, we propose our working hypothesis that OMVs produced in chronic HP infection in the gut induce neuroinflammation in the CNS, explaining the higher prevalence of AD in HP-infected people.
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Kazuki Hashiwaki; Ikuo Tsunoda
    Scientific reports 12 (1) 11361 - 11361 2022/07 [Refereed]
     
    The COVID-19 pandemic has led people to wear face masks daily in public. Although the effectiveness of face masks against viral transmission has been extensively studied, there have been few reports on potential hygiene issues due to bacteria and fungi attached to the face masks. We aimed to (1) quantify and identify the bacteria and fungi attaching to the masks, and (2) investigate whether the mask-attached microbes could be associated with the types and usage of the masks and individual lifestyles. We surveyed 109 volunteers on their mask usage and lifestyles, and cultured bacteria and fungi from either the face-side or outer-side of their masks. The bacterial colony numbers were greater on the face-side than the outer-side; the fungal colony numbers were fewer on the face-side than the outer-side. A longer mask usage significantly increased the fungal colony numbers but not the bacterial colony numbers. Although most identified microbes were non-pathogenic in humans; Staphylococcus epidermidis, Staphylococcus aureus, and Cladosporium, we found several pathogenic microbes; Bacillus cereus, Staphylococcus saprophyticus, Aspergillus, and Microsporum. We also found no associations of mask-attached microbes with the transportation methods or gargling. We propose that immunocompromised people should avoid repeated use of masks to prevent microbial infection.
  • Noriomi Matsumura; Ikuo Tsunoda
    Cancer science 113 (10) 3313 - 3320 2022/07 [Refereed]
     
    Cervical cancer is caused by infections of the human papillomavirus (HPV), which can be preventable by vaccinations. In Japan, although about 3,000 people died of cervical cancer annually, the HPV vaccination rate has remained extremely low in the eligible population, since many Japanese have been concerned that "diverse symptoms," such as chronic pain, movement disorders, and cognitive impairment, may occur as adverse reactions after HPV vaccination. The concern has been raised by media coverage of the ongoing HPV vaccine lawsuits, in which the plaintiffs complained of their symptoms caused by HPV vaccination. The claims have been based on the alleged pathogenic findings in research articles on HPV vaccines, summarized in the document prepared by the plaintiffs' attorneys. We critically evaluated these articles, in which the authors proposed the following findings/hypothesis: (i) molecular mimicry between HPV L1 and human proteins leads to the production of cross-reactive antibodies; and (ii) HPV vaccine injection in mice causes damage in the brain, a mouse model for "HPV vaccine associated neuro-immunopathic syndrome (HANS)." We found that they were based mainly on the findings from a few research groups and that all the articles had flaws in the method, result, or discussion sections. Our current evaluation would help better understand the validity of the findings, which have been often misunderstood as the truth by the general public. We propose to accumulate high-quality data on potential adverse events following HPV vaccination and to continue critically evaluating them.
  • M Hafedh; AH Parnow; C Jalili; D I. Patel; I Tsunoda
    Journal of Advanced Biomedical Sciences Knowledge E 12 (4) 4068 - 4076 2783-1523 2022/02 [Refereed]
     
    Background & objective: Exercise has been shown to improve cognitive function in patients with multiple sclerosis (MS). Experimentally, glucocorticoids (GCs) treatment has been observed to improve cognitive deterioration in an autoimmune model for MS, experimental autoimmune encephalomyelitis (EAE). We aimed to determine the combined effect of exercise and 4 mg/kg of dexamethasone (Dex) for 4 weeks on spatial memory in EAE. Materials & Methods: Rats with EAE were subjected to the Morris water maze (MWM) for four days and a prop test for one day. The prop test was repeated on day 40 post-induction (dpi). Rats were randomly assigned to one of four groups (10 rats per group): control EAE without treatment; EAE + dexamethasone, (EAE + Dex); EAE + exercise (EAE + Ex); and EAE+Dex+Ex. Rats receiving dexamethasone were administered 4 mg/kg injections daily for two weeks after EAE induction. Exercise training was initiated on a motorized treadmill 2 weeks before EAE induction and continued until 14 dpi. On day 41, animals were dissected and CORT level was assessed by enzyme-linked immunosorbent assay corticosterone kit. Results: One-way analysis of variance (ANOVA) with repeated measures followed by a protected LSD post hoc test indicated that, EAE+Ex group increased body weight (P < 0.001) and it displayed a significantly lower CORT concentration (P <0.001) with delayed clinical score until day 13 dpi. Further EAE+Ex improved memory by time spent (p > 0.001) and swimming speed (p>0.002). Conclusion: The protocol selected in this study was an effective treatment for the EAE model to improve spatial memory and regulate corticosterone concentrations.
  • Fumitaka Sato; Yumina Nakamura; Aoshi Katsuki; Sundar Khadka; Ijaz Ahmad; Seiichi Omura; Nicholas E. Martinez; Ikuo Tsunoda
    Frontiers in Cellular and Infection Microbiology Frontiers Media SA 12 805302 - 805302 2022/02 [Refereed][Invited]
     
    Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and axonal degeneration in the central nervous system (CNS). Bacterial and fungal infections have been associated with the development of MS; microbial components that are present in several microbes could contribute to MS pathogenesis. Among such components, curdlan is a microbial 1,3-β-glucan that can stimulate dendritic cells, and enhances T helper (Th) 17 responses. We determined whether curdlan administration could affect two animal models for MS: an autoimmune model, experimental autoimmune encephalomyelitis (EAE), and a viral model, Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). We induced relapsing-remitting EAE by sensitizing SJL/J mice with the myelin proteolipid protein (PLP)139-151 peptide and found that curdlan treatment prior to PLP sensitization converted the clinical course of EAE into hyperacute EAE, in which the mice developed a progressive motor paralysis and died within 2 weeks. Curdlan-treated EAE mice had massive infiltration of T cells and neutrophils in the CNS with higher levels of Th17 and Th1 responses, compared with the control EAE mice. On the other hand, in TMEV-IDD, we found that curdlan treatment reduced the clinical scores and axonal degeneration without changes in inflammation or viral persistence in the CNS. In summary, although curdlan administration exacerbated the autoimmune MS model by enhancing inflammatory demyelination, it suppressed the viral MS model with reduced axonal degeneration. Therefore, microbial infections may play contrasting roles in MS depending on its etiology: autoimmunity versus viral infection.
  • Sundar Khadka; Seiichi Omura; Fumitaka Sato; Kazuto Nishio; Hideaki Kakeya; Ikuo Tsunoda
    Frontiers in Cellular and Infection Microbiology Frontiers Media SA 11 2021/12 [Refereed]
     
    We developed a prodrug type of curcumin, curcumin monoglucuronide (CMG), whose intravenous/intraperitoneal injection achieves a high serum concentration of free-form curcumin. Although curcumin has been reported to alter the gut microbiota and immune responses, it is unclear whether the altered microbiota could be associated with inflammation in immune-mediated diseases, such as multiple sclerosis (MS). We aimed to determine whether CMG administration could affect the gut microbiota at three anatomical sites (feces, ileal contents, and the ileal mucosa), leading to suppression of inflammation in the central nervous system (CNS) in an autoimmune model for MS, experimental autoimmune encephalomyelitis (EAE). We injected EAE mice with CMG, harvested the brains and spinal cords for histological analyses, and conducted microbiome analyses using 16S rRNA sequencing. CMG administration modulated EAE clinically and histologically, and altered overall microbiota compositions in feces and ileal contents, but not the ileal mucosa. Principal component analysis (PCA) of the microbiome showed that principal component (PC) 1 values in ileal contents, but not in feces, correlated with the clinical and histological EAE scores. On the other hand, when we analyzed the individual bacteria of the microbiota, the EAE scores correlated with significant increases in the relative abundance of two bacterial species at each anatomical site: Ruminococcus bromii and Blautia (Ruminococcus) gnavus in feces, Turicibacter sp. and Alistipes finegoldii in ileal contents, and Burkholderia spp. and Azoarcus spp. in the ileal mucosa. Therefore, CMG administration could alter the gut microbiota at the three different sites differentially in not only the overall gut microbiome compositions but also the abundance of individual bacteria, each of which was associated with modulation of neuroinflammation.
  • Ikuo Tsunoda
    Adolescentology 日本思春期学会 39 (1) 20 - 27 2021/03 [Invited]
     
    子宮頸がんの予防に有効なヒトパピローマウ イ ル ス(HPV)ワ ク チ ン は、 神 経 系 に お こるとされる「副反応」への偏向した報道などから、日本での接種率は極めて低い。一般的にワクチン接種によって誘導され得る免疫性の神経障害の機序には、1)分子相同性、2)バイスタンダー・キリング、3)エピトープ・スプレッディングがある。本稿では、これら3つの機序を代表的な基礎実験系をもとに概説する。また、HPVワクチン接種ではいずれの機序も起こり得 ないことを、神経免疫学・ウイルス学の専門家の立場から解説するとともに、子宮頸がんワクチン関連神経免疫異常症候群(HANS)の理論的虚構を明らかにする。
  • 角田郁生
    産婦人科の実際 金原出版株式会社 70 (3) 305 - 312 2021/03 [Refereed][Invited]
     
    子宮頸がんはヒトパピローマウイルス(HPV)感染が原因であり、HPVワクチン接種により予防できる。しかしながら、日本ではHPVワクチンによる神経系の“副反応”とされる子宮頸がんワクチン関連神経免疫異常症候群 (HANS) を再現したとする動物実験系が広く報道されたことなどから、ワクチン接種率が1%以下に落ち込んでいる。本稿では、HANSという概念が国際科学誌上で認知されていないこと、HANSの動物モデルとして発表されたデータには科学的に問題があることを基礎医学の立場から解説する。また、一般的にワクチンで起こり得る神経障害の機序についても概説する。
  • Sundar Khadka; Ikuo Tsunoda
    Encyclopedia MDPI 2021 [Refereed]
  • Yumina Nakamura; Ah-Mee Park; Ikuo Tsunoda
    別冊 BIO Clinica 北隆館 25 98 - 102 2020/12 [Refereed][Invited]
     
    IgA は粘膜免疫の主体として知られるが, タイラーウイルス(TMEV)による多発性硬化症のマウスモデルにおいては, IgAは意外にも脊髄の炎症性脱髄病巣に一致して検出される。本稿では IgA の経時的モニタリングのために、我々が開発した簡便なマウス唾液採取法を紹介する。この手技の確立は TMEV モデルの病態解明に有用であるだけでなく, 唾液からのウイルスおよび IgA の検出が開発の鍵となる新型コロナウイルス・ワクチンにも貢献し得る。 助成:日本学術振興会 基盤研究 (C) [18K07379 (A-MP) 20K07455(IT)]・新学術領域 [17H06404 (IT)], 日本医療研究開発機構 (AMED) 新興・再興感染症に対する革新的医薬品等開発推進研究事業 [20fk0108084h0802 (IT), 19fk0108168s0101 (IT)],令和 2 年度“オール近大”新型コロナウイルス感染症対策支援プロジェクト 研究11 (IT) 研究16 (A-MP)
  • Sundar Khadka; Roshan Pandit; Subhash Dhital; Jagat Bahadur Baniya; Surendra Tiwari; Bimal Shrestha; Sanjeet Pandit; Fumitaka Sato; Mitsugu Fujita; Mukunda Sharma; Ikuo Tsunoda; Shravan Kumar Mishra
    Pathophysiology MDPI AG 27 (1) 3 - 13 2020/11 [Refereed][Invited]
     
    Hepatitis B virus (HBV) infects the liver, causing cirrhosis and cancer. In developed countries, five international guidelines have been used to make a decision for the management of patients with chronic HBV infection. In this review, since the guidelines were established by clinical and epidemiological data of developed countries, we aimed to evaluate whether (1) HBV patient profiles of developing countries are similar to developed countries, and (2) which guideline can be applicable to resource-limited developing countries. First, as an example of the most recent data of HBV infections among developing countries, we evaluated the national HBV viral load study in Nepal, which were compared with the data from other developing countries. In Nepal, the highest number of patients had viral loads of 20–2000 IU/mL (36.7%) and belonged to the age group of 21–30 years; HBV epidemiology in Nepal, based on the viral loads, gender, and age groups was similar to those of not only other developing countries but also developed countries. Next, we reviewed five international HBV treatment guidelines of the World Health Organization (WHO), American Association for the Study of Liver Diseases (AASLD), National Institute for Health and Care Excellence (NICE), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). All guidelines require the viral load and alanine aminotransferase (ALT) levels for decision making. Although four guidelines recommend elastography to assess liver cirrhosis, the WHO guideline alternatively recommends using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), which is inexpensive and conducted routinely in most hospitals. Therefore, in resource-limited developing countries like Nepal, we recommend the WHO guideline for HBV treatment based on the viral load, ALT, and APRI information.
  • 感染によって誘発される神経免疫病態 タイラーウイルスによる急性灰白脳脊髄炎・多発性硬化症動物モデル 分子相同性から腸内細菌叢まで
    角田 郁生; 尾村 誠一; 佐藤 文孝; 崎山 奈美江; Khadka Sundar; 中村 優美和; 朴 雅美; 藤田 貢
    神経免疫学 日本神経免疫学会 25 (1) 67 - 67 0918-936X 2020/10
  • プロドラッグ型クルクミンCMGによる実験的自己免疫性脳脊髄炎の抑制と小腸細菌叢変化
    佐藤 文孝; カドカ・スンダル; 尾村 誠一; 朴 雅美; 藤田 貢; 中村 優美和; 西尾 和人; 掛谷 秀昭; 角田 郁生
    神経免疫学 日本神経免疫学会 25 (1) 100 - 100 0918-936X 2020/10
  • Ah-Mee Park; Sundar Khadka; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Daniel K. Hsu; Fu-Tong Liu; Ikuo Tsunoda
    Frontiers in Immunology Frontiers Media SA 11 550366 - 550366 2020/09 [Refereed]
     
    Non-steroidal anti-inflammatory drugs (NSAIDs) induce ulcers in the gastrointestinal tract, including the stomach and small intestine. NSAID-induced gastric ulcers can be prevented by taking acid-neutralizing/inhibitory drugs and cytoprotective agents. In contrast, there are no medicines to control NSAID-induced small intestinal ulcers, which are accompanied by a mucosal invasion of bacteria and subsequent activation of immune cells. Galectin-3 (Gal3), an endogenous lectin, has anti-microbial and pro-inflammatory functions. In the small intestine, since Gal3 is highly expressed in epithelial cells constitutively and macrophages inducibly, the Gal3 level can affect microbiota composition and macrophage activation. We hypothesized that the modulation of Gal3 expression could be beneficial in NSAID-induced intestinal ulcers. Using Gal3 knockout (Gal3KO) mice, we determined whether Gal3 could be a therapeutic target in NSAID-induced intestinal ulcers. Following the administration of indomethacin, an NSAID, we found that small intestinal ulcers were less severe in Gal3KO mice than in wild-type (WT) mice. We also found that the composition of intestinal microbiota was different between WT and Gal3KO mice and that bactericidal antibiotic polymyxin B treatment significantly suppressed NSAID-induced ulcers. Furthermore, clodronate, a macrophage modulator, attenuated NSAID-induced ulcers. Therefore, Gal3 could be an exacerbating factor in NSAID-induced intestinal ulcers by affecting the intestinal microbiota population and macrophage activity. Inhibition of Gal3 may be a therapeutic strategy in NSAID-induced intestinal ulcers. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03832946.
  • 胃粘膜ヘリコバクター・ピロリ菌感染によるCNS内神経炎症の誘導
    朴雅美; 角田郁生
    Medical Science Digest 46 (10) 566 - 567 2020/09 [Refereed]
  • Ikuo Tsunoda
    Frontiers in Medicine Frontiers Media SA 7 377  2020/07 [Refereed]
     
    On March 26, 2019, Dr. Riko Muranaka was found guilty of libel by a Japanese court for her claim that Dr. Shuichi Ikeda had fabricated data suggesting that the human papillomavirus vaccine can cause brain damage in mice. Because of the negative publicity that this trial has given to HPV vaccination efforts, we summarize and evaluate the documents submitted to the trial from a scientific standpoint. Based on the evidence, we conclude that there is no proof that the HPV vaccine could induce brain damage in the hippocampus of experimental mice. This conclusion is based on of lack of information about the number of mice used in the first experiment as well as the negative result of the second experiment conducted by the same group. Based on such inconclusive experimental findings, no credible scientist can accept the possibility of the "adverse effect" of HPV vaccine.
  • Seiichi Omura; Fumitaka Sato; Ah-Mee Park; Mitsugu Fujita; Sundar Khadka; Yumina Nakamura; Aoshi Katsuki; Kazuto Nishio; Felicity N. E. Gavins; Ikuo Tsunoda
    Frontiers in Immunology Frontiers Media SA 11 1138 - 1138 2020/07 [Refereed]
     
    Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.
  • J. W. Yun; U. Cvek; P. C.S.R. Kilgore; I. Tsunoda; S. Omura; F. Sato; R. Zivadinov; M. Ramanathan; A. Minagar; J. S. Alexander
    Life Sciences Elsevier BV 229 116 - 123 0024-3205 2019/07 [Refereed]
     
    © 2019 Aims: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. Main methods: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. Key findings: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. Significance: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.
  • Seiichi Omura; Fumitaka Sato; Nicholas E. Martinez; Ah-Mee Park; Mitsugu Fujita; Nikki J. Kennett; Urška Cvek; Alireza Minagar; J. Steven Alexander; Ikuo Tsunoda
    Frontiers in Immunology Frontiers Media SA 10 516 - 516 1664-3224 2019/03 [Refereed]
     
    Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the homogeneity and heterogeneity of two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational analyses. We identified up-regulation of immune-related genes, including immunoglobulins, in the CNS of both models. Pro-inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-17, were associated with the disease progression in SJL/J mice, while the expression of both cytokines was detected only at the EAE onset in A.SW mice. Principal component analysis (PCA) of CNS transcriptome data demonstrated that down-regulation of prolactin may reflect disease progression. Pattern matching analysis of spleen transcriptome with CNS PCA identified 333 splenic surrogate markers, including Stfa2l1, which reflected the changes in the CNS. Among them, we found that two genes (PER1/MIR6883 and FKBP5) and one gene (SLC16A1/MCT1) were also significantly up-regulated and down-regulated, respectively, in human MS peripheral blood, using data mining.
  • Seiichi Omura; Eiichiro Kawai; Fumitaka Sato; Nicholas E. Martinez; Alireza Minagar; Mahmoud Al-Kofahi; J. Winny Yun; Urska Cvek; Marjan Trutschl; J. Steven Alexander; Ikuo Tsunoda
    Frontiers in Immunology Frontiers Media SA 9 2870 - 2870 1664-3224 2018/12 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, with cytokines playing key roles for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord about 1 month post-inoculation (p.i.). Unlike other immunopathology models, both pro- and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play beneficial roles in viral clearance while they are also detrimental in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. Conversely, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three distinctive phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the exact mechanism(s) by which a single virus, TMEV, induces these different diseases in different organs is unclear, our bioinformatics approaches, especially principal component analysis (PCA) of transcriptome data, allow us to identify the key factors contributing to organ-specific immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line reproduced the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in TMEV-infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of the in vivo CNS transcriptome data showed that decreased lymphatic marker expressions were weakly associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels is shown to potentially contribute to immunopathology by delaying the clearance of cytokines and immune cells from the inflammatory site, although this can also confine the virus at these sites, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility provoked by pro-inflammatory cytokines. Therefore, TMEV infection may induce different patterns of cytokine expressions as well as lymphatic vessel dysfunction by rather different mechanisms between the CNS and heart, which might explain observed patterns of organ-specific immunopathology.
  • Al-Kofahi M; Omura S; Tsunoda I; Sato F; Becker F; Gavins FNE; Woolard MD; Pattillo C; Zawieja D; Muthuchamy M; Gashev A; Shihab I; Ghoweba M; Von der Weid PY; Wang Y; Alexander JS
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 107 1591 - 1600 0753-3322 2018/11 [Refereed]
     
    The role of lymphatic vessels in myocarditis is largely unknown, while it has been shown to play a key role in other inflammatory diseases. We aimed to investigate the role of lymphatic vessels in myocarditis using in vivo model induced with Theiler's murine encephalomyelitis virus (TMEV) and in vitro model with rat cardiac lymphatic muscle cells (RCLMC). In the TMEV model, we found that upregulation of a set of inflammatory mediator genes, including interleukin (IL)-1β, tumor necrosis factor (TNF)-αand COX-2 were associated with disease activity. Thus, using in vitro collagen gel contraction assays, we decided to clarify the role(s) of these mediators by testing contractility of RCLMC in response to IL-1β and TNF-α individually and in combination, in the presence or absence of: IL-1 receptor antagonist (Anakinra); cyclooxygenase (COX) inhibitors inhibitors (TFAP, diclofenac and DuP-697). IL-1β impaired RCLMC contractility dose-dependently, while co-incubation with both IL-1β and TNF-α exhibited synergistic effects in decreasing RCLMC contractility with increased COX-2 expression. Anakinra maintained RCLMC contractility; Anakinra blocked the mobilization of COX-2 induced by IL-1β with or without TNF-α. COX-2 inhibition blocked the IL-1β-mediated decrease in RCLMC contractility. Mechanistically, we found that IL-1β increased prostaglandin (PG) E2 release dose-dependently, while Anakinra blocked IL-1β mediated PGE2 release. Using prostaglandin E receptor 4 (EP4) receptor antagonist, we demonstrated that EP4 receptor blockade maintained RCLMC contractility following IL-1β exposure. Our results indicate that IL-1β reduces RCLMC contractility via COX-2/PGE2 signaling with synergistic cooperation by TNF-α. These pathways may help provoke inflammatory mediator accumulation within the heart, driving progression from acute myocarditis into dilated cardiomyopathy.
  • Park AM; Tsunoda I
    BioTechniques 65 (4) 227 - 230 0736-6205 2018/08 [Refereed]
     
    Fecal occult blood (FOB) is a sign of gastrointestinal diseases, such as intestinal ulcers and colorectal cancer. In experimental animal studies, there is no standard method to detect FOB. Here, we present a simple protocol to detect FOB in mice, using the Luminol Reaction Experiment Kit® that was originally designed to detect bloodstains at a crime scene in criminal forensics. To obtain positive control bloody feces, we used an indomethacin-induced intestinal ulcer model in mice. By mixing small pieces of feces with a luminol solution, the fecal solution emitted visible blue-white chemiluminescence in dark field when feces contained hemoglobin. We also established a method for semi-quantification of hemoglobin content in the fecal solution, using a luminometer. This method is simple, quick, economical and semi-quantitative, allowing researchers to detect FOB in experimental mice.
  • Park AM; Tsunoda I; Yoshie O
    The Journal of biological chemistry 293 (41) 15815 - 15826 0021-9258 2018/08 [Refereed]
     
    Heat shock protein 27 (HSP27) protects cells under stress. Here, we demonstrate that HSP27 also promotes cell cycle progression of MRC-5 human lung fibroblast cells. Serum starvation for 24 h induced G1 arrest in these cells, and upon serum refeeding, the cells initiated cell cycle progression accompanied by an increase in HSP27 protein levels. HSP27 levels peaked at 12 h, and transcriptional up-regulation of six G2/M-related genes (CCNA2, CCNB1, CCNB2, CDC25C, CDCA3, and CDK1) peaked at 24-48 h. siRNA-mediated HSP27 silencing in proliferating MRC-5 cells induced G2 arrest coinciding with down-regulation of these six genes. Of note, the promoters of all of these genes have the cell cycle-dependent element and/or the cell cycle gene-homology region. These promoter regions are known to be bound by the E2F family proteins (E2F-1 to E2F-8) and retinoblastoma (RB) family proteins (RB1, p107, and p130), among which E2F-4 and p130 were strongly up-regulated in HSP27-knockdown cells. E2F-4 or p130 knockdown concomitant with the HSP27 knockdown rescued MRC-5 cells from G2 arrest and up-regulated the six cell cycle genes. Moreover, we observed cellular senescence in MRC-5 cells on day 3 after the HSP27 knockdown, as evidenced by increased senescence-associated β-gal activity and up-regulated inflammatory cytokines. The cellular senescence was also suppressed by the concomitant knockdown of E2F-4/HSP27 or p130/HSP27. Our findings indicate that HSP27 promotes cell cycle progression of MRC-5 cells by suppressing expression of the transcriptional repressors E2F-4 and p130.
  • Helen K. Smith; Seiichi Omura; Shantel A. Vital; Felix Becker; Elena Y. Senchenkova; Gaganpreet Kaur; Ikuo Tsunoda; Shayn M. Peirce; Felicity N. E. Gavins
    FASEB Journal FASEB 32 (5) 2381 - 2394 1530-6860 2018/05 [Refereed]
     
    Stroke continues to be a leading cause of death and disability worldwide, yet effective treatments are lacking. Previous studies have indicated that stem-cell transplantation could be an effective treatment. However, little is known about the direct impact of transplanted cells on injured brain tissue. We wanted to help fill this knowledge gap and investigated effects of hematopoietic stem/progenitor cells (HSPCs) on the cerebral microcir-culation after ischemia-reperfusion injury (I/RI). Treatment of HSPCs in I/RI for upto 2 wk after cerebral I/RI led to decreased mortality rate, decreased infarct volume, improved functional outcome, reduced microglial activation, and reduced cerebral leukocyte adhesion. Confocal microscopy and fluorescence-activated cell sorting analyses showed transplanted HSPCs emigrate preferentially into ischemic cortex brain parenchyma. We isolated migrated HSPCs from the brain using RNA sequencing to investigate the transcriptome, we found metallothionein (MT, particularly MT-I) transcripts were dramatically up-regulated. Finally, to confirm the significance of MT, we ex-ogenously administered MT-I after cerebral I/RI and found that it produced neuroprotection in a manner similar to HSPC treatment. These findings provide novel evidence that the mechanism through which HSPCs promote repair after stroke maybe via direct action of HSPC-derived MT-I and could therefore be exploited as a useful therapeutic strategy for stroke.
  • Seiichi Omura; Fumitaka Sato; Nicholas E. Martinez; Tierra Range; Lesya Ekshyyan; Alireza Minagar; J. Steven Alexander; Ikuo Tsunoda
    Archives of Virology Springer-Verlag Wien 163 (5) 1279 - 1284 0304-8608 2018/05 [Refereed]
     
    While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler’s murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection.
  • Kyosuke Kanai; Ah-Mee Park; Akiko Watanabe; Tomohiro Arikawa; Teruhito Yasui; Hiroki Yoshida; Ikuo Tsunoda; Osamu Yoshie
    Journal of Immunology American Association of Immunologists 200 (8) 2703 - 2713 1550-6606 2018/04 [Refereed]
     
    IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27–deficient mice), we examined the role of IL-27 in primary infection by murine g-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27–deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27–deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27–deficient mice was characterized by more IFN-g–producing CD8+ T cells and fewer IL-10–producing CD8+ T cells than that of wild-type mice. An infectious mononucleosis–like disease was also aggravated in IL-27–deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-g–producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10–producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis.
  • Jaebok Choi; Matthew L. Cooper; Karl Staser; Kidist Ashami; Kiran R. Vij; Bing Wang; Lynne Marsala; Jessica Niswonger; Julie Ritchey; Bader Alahmari; Samuel Achilefu; Ikuo Tsunoda; Mark A. Schroeder; John F. DiPersio
    Leukemia Nature Publishing Group 32 (11) 1 - 12 1476-5551 2018/04 [Refereed]
     
    The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need. We demonstrate that the dual inhibition of interferon gamma receptor (IFNγR) and interleukin-6 receptor (IL6R) results in near-complete elimination of GvHD in a fully major histocompatibility complex–mismatched allo-HSCT model. Furthermore, baricitinib (an inhibitor of Janus kinases 1 and 2 (JAK1/JAK2) downstream of IFNγR/IL6R) completely prevented GvHD expanded regulatory T cells by preserving JAK3-STAT5 signaling downregulated CXCR3 and helper T cells 1 and 2 while preserving allogeneic antigen-presenting cell-stimulated T-cell proliferation and suppressed the expression of major histocompatibility complex II (I-Ad), CD80/86, and PD-L1 on host antigen-presenting cells. Baricitinib also reversed established GvHD with 100% survival, thus demonstrating both preventive and therapeutic roles for this compound. Remarkably, baricitinib enhanced the GvL effects, possibly by downregulating tumor PD-L1 expression.
  • Kazuhiko Matsuo; Daisuke Nagakubo; Shinya Yamamoto; Akiko Shigeta; Shuta Tomida; Mitsugu Fujita; Takako Hirata; Ikuo Tsunoda; Takashi Nakayama; Osamu Yoshie
    Journal of immunology (Baltimore, Md. : 1950) 200 (2) 800 - 809 0022-1767 2018/01 [Refereed]
     
    CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.
  • Fumitaka Sato; Eiichiro Kawai; Nicholas E. Martinez; Seiichi Omura; Ah-Mee Park; Satoru Takahashi; Keigyou Yoh; Ikuo Tsunoda
    SCIENTIFIC REPORTS NATURE PUBLISHING GROUP 7 (1) 10496  2045-2322 2017/09 [Refereed]
     
    Intracerebral Theiler's murine encephalomyelitis virus (TMEV) infection in mice induces inflammatory demyelination in the central nervous system. Although C57BL/6 mice normally resistant to TMEV infection with viral clearance, we have previously demonstrated that ROR gamma t-transgenic (tg) C57BL/6 mice, which have Th17-biased responses due to ROR gamma t overexpression in T cells, became susceptible to TMEV infection with viral persistence. Here, using T-bet-tg C57BL/6 mice and Gata3-tg C57BL/6 mice, we demonstrated that overexpression of T-bet, but not Gata3, in T cells was detrimental in TMEV infection. Unexpectedly, T-bet-tg mice died 2 to 3 weeks after infection due to failure of viral clearance. Here, TMEV infection induced splenic T cell depletion, which was associated with lower anti-viral antibody and T cell responses. In contrast, Gata3-tg mice remained resistant, while Gata3-tg mice had lower IFN-gamma and higher IL-4 production with increased anti-viral IgG1 responses. Thus, our data identify how overexpression of T-bet and Gata3 in T cells alters anti-viral immunity and confers susceptibility to TMEV infection.
  • Ah-Mee Park; Seiichi Omura; Mitsugu Fujita; Fumitaka Sato; Ikuo Tsunoda
    Clinical & experimental neuroimmunology 8 (3) 215 - 232 2017/08 [Refereed][Invited]
     
    Alteration of microbiota has been associated with intestinal, inflammatory, and neurological diseases. Abundance of "good bacteria" such as Bifidobacterium, or their products have been generally believed to be beneficial for any diseases, while "bad bacteria" such as pathogenic Helicobacter pylori are assumed to be always detrimental for hosts. However, this is not the case when we compare and contrast the association of the gut microbiota with two neurological diseases, multiple sclerosis (MS) and Alzheimer's disease (AD). Following H. pylori infection, pro-inflammatory T helper (Th)1 and Th17 immune response are initially induced to eradicate bacteria. However, H. pylori evades the host immune response by inducing Th2 cells and regulatory T cells (Tregs) that produce anti-inflammatory interleukin (IL)-10. Suppression of anti-bacterial Th1/Th17 cells by Tregs may enhance gastric H. pylori propagation, followed by a cascade reaction involving vitamin B12 and folic acid malabsorption, plasma homocysteine elevation, and reactive oxygen species induction. This can damage the blood-brain barrier (BBB), leading to accumulation of amyloid-β in the brain, a hallmark of AD. On the other hand, this suppression of pro-inflammatory Th1/Th17 responses to H. pylori has protective effects on the hosts, since it prevents uncontrolled gastritis as well as suppresses the induction of encephalitogenic Th1/Th17 cells, which can mediate neuroinflammation in MS. The above scenario may explain why chronic H. pylori infection is positively associated with AD, while it is negatively associated with MS. Lastly, we list "10 pitfalls of microbiota studies", which will be useful for evaluating and designing clinical and experimental microbiota studies.
  • Ikuo Tsunoda
    Clinical and Experimental Neuroimmunology Wiley-Blackwell 8 (3) 177 - 179 1759-1961 2017/08 [Refereed][Invited]
  • 感染因子による神経免疫疾患誘発のメカニズムと治療 ウイルス感染によって誘導される"軸索型"多発性硬化症動物モデル インサイド-アウト・モデル
    角田 郁生; 尾村 誠一; 佐藤 文孝; 崎山 奈美江; 朴 雅美; 藤田 貢
    NEUROINFECTION 日本神経感染症学会 22 (1) 28 - 35 1348-2718 2017/04 [Refereed]
     
    多発性硬化症(multiple sclerosis、MS)は中枢神経系の炎症性脱髄と軸索障害を主体とする神経変性疾患であり、全世界では200万人以上、日本では約1万人のMS患者が存在する。MS発症の原因としてはウイルス感染説と自己免疫説が提唱されている。その動物実験モデルとして、前者に対してはタイラーウイルス誘導性脱髄疾患[Theiler's murine encephalomyelitis virus(TMEV)-induced demyelinating disease、TMEV-IDD]が、後者に対しては実験的自己免疫性脳脊髄炎(experimental autoimmune encephalomyelitis、EAE)が、それぞれ頻用されている。両者ともT細胞が病変形成に関与するが、MS様病変である脱髄と軸索変性の進展様式は両者間で異なる。TMEV-IDDでは、病変は神経線維の内側(インサイド)の軸索障害に始まり、外側(アウトサイド)の髄鞘障害(=脱髄)へと進展する(インサイド-アウト・モデル)。一方、EAEでは外側の髄鞘障害が先行し、続いて内側の軸索障害が誘導される(アウトサイド-イン・モデル)。ヒトMSの病理像では、インサイド-アウト・モデルとアウトサイド-イン・モデルそれぞれに合致する病理像が報告されており、前者は"軸索型"MSといえるものであり、後者の古典的"脱髄型"MSとは異なる。また両者の病理像が同一個体でみられるMS症例も存在する。すなわち"インサイド-アウト"と"アウトサイド-イン"の進展様式は相反するものではなく、むしろ共存して悪循環を形成し病態進行に寄与しうると推測される。この悪循環を断つ方法としては、1)炎症抑制、2)軸索保護、3)軸索変性の抑制(ウイルス感染の場合は、ウイルス増殖抑制による)の三つが考えられる。理論的には、この悪循環のいずれかのステップに介入する治療法がMSの進行抑制を可能にする。実際、MS治療に作用点の異なる複数の薬剤が有効であるという臨床データが、MS症例の多くで前述二つの進展様式が共存しうることを示唆する。(著者抄録)
  • Sato F; Omura S; Park A. M; Fujita M; Stokes K; Tsunoda I
    Journal of the Neurological Sciences Elsevier BV 381 1057 - 1058 0022-510X 2017 [Refereed]
  • Influx and efflux of immune cells in the central nervous system.
    Fujita M; Omura S; Sato F; Park A.-M; Tsunoda I
    Anat. Physiol. 7 274  2017 [Refereed][Invited]
  • Kyosuke Kanai; Ah-Mee Park; Hiroki Yoshida; Ikuo Tsunoda; Osamu Yoshie
    JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 198 (1) 119 - 127 0022-1767 2017/01 [Refereed]
     
    EBI3 functions as the subunit of immune-regulatory cytokines, such as IL-27 and IL-35, by pairing with p28 and p35, respectively. We treated wild-type and EBI3-deficient mice with intratracheal administration of LPS and obtained bronchoalveolar lavage fluid (BALF) 24 h later. Although neutrophils were the predominant cells in BALF from both groups of mice, eosinophils were highly enriched and there was increased production of eosinophil-attracting chemokines CCL11 and CCL24 in BALF of EBI3-deficient mice. The bronchial epithelial cells and alveolar macrophages were the major producers of CCL11 and CCL24. Because no such increases in eosinophils were seen in BALF of p28/IL-27-deficient mice or WSX-1/IL-27Ra subunit-deficient mice upon intratracheal stimulation with LPS, we considered that the lack of IL-35 was responsible for the enhanced airway eosinophilia in EBI3-deficient mice. In vitro, IL-35 potently suppressed production of CCL11 and CCL24 by human lung epithelial cell lines treated with TNF-alpha and IL-1 beta. IL-35 also suppressed phosphorylation of STAT1 and STAT3 and induced suppressor of cytokine signaling 3. In vivo, rIL-35 dramatically reduced LPS-induced airway eosinophilia in EBI3-deficient mice, with concomitant reduction of CCL11 and CCL24, whereas neutralization of IL-35 significantly increased airway eosinophils in LPS-treated wild-type mice. Collectively, our results suggest that IL-35 negatively regulates airway eosinophilia, at least in part by reducing the production of CCL11 and CCL24.
  • 角田郁生
    近畿大学医学雑誌 近畿大学医学会 41 (3-4) 7A - 9A 0385-8367 2016/12 [Refereed]
  • J. Winny Yun; Adam Xiao; Ikuo Tsunoda; Alireza Minagar; J. Steven Alexander
    Pathophysiology Elsevier B.V. 23 (4) 265 - 274 1873-149X 2016/12 [Refereed]
     
    Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular ‘trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in ‘liquid biopsy’ approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer's disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases.
  • Ikuo Tsunoda; Fumitaka Sato; Seiichi Omura; Mitsugu Fujita; Namie Sakiyama; Ah-Mee Park
    Clinical & experimental neuroimmunology Wiley-Blackwell 7 (4) 330 - 345 1759-1961 2016/11 [Refereed][Invited]
     
    Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a viral model for multiple sclerosis (MS), as TMEV can induce chronic inflammatory demyelinating lesions with viral persistence in the spinal cord of SJL/J mice. In contrast, when C57BL/6 mice are infected with TMEV, the mice can clear the virus from the central nervous system (CNS), without viral persistence or demyelination, but develop seizures and hippocampal sclerosis, which has been used as a viral model for seizures/epilepsy. In the two TMEV-induced CNS disease models, not only viral infection, but also immune responses contribute to the pathogenesis. Interestingly, acquired immunity plays an effector role in the MS model, whereas innate immunity appears to contribute to the development of seizures. Recently, we have established the third TMEV-induced disease model, a mouse model for viral myocarditis, using C3H mice. TMEV-induced myocarditis is a triphasic disease, which mimics human myocarditis; phase I, mediated by viral replication in the heart and innate immunity; phase II, mediated by acquired immunity; and phase III, resulted from cardiac fibrosis. The genetic susceptibility to the aforementioned three models (MS, seizures and myocarditis) differs among mouse strains. We have compared and contrasted the three models induced by one single pathogen, TMEV, particularly in regard to the roles of T helper cells and natural killer T cells, which will give an insight into how interactions between the immune system and the host's genetic background determine the tissue tropism of virus and the development of virus-induced organ-specific immunopathology.
  • Felix Becker; Elvira Kurmaeva; Felicity N. E. Gavins; Emily V. Stevenson; Aaron R. Navratil; Long Jin; Ikuo Tsunoda; A. Wayne Orr; Jonathan S. Alexander; Dmitry V. Ostanin
    INFLAMMATORY BOWEL DISEASES LIPPINCOTT WILLIAMS & WILKINS 22 (6) 1326 - 1345 1078-0998 2016/06 [Refereed]
     
    Background:Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (M) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/M to the development of intestinal inflammation and IAL.Methods:Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2(-/-) mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4(+)CD45RB(high) T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density.Results:We demonstrated that intestinal M phi expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2(-/-) mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL.Conclusions:We propose a dual role of M phi in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/M phi, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of M phi independently, to restore lymphatic clearance and reduce inflammation.
  • J. Winny Yun; Alireza Minagar; Ikuo Tsunoda; J. Steven Alexander
    FASEB JOURNAL FEDERATION AMER SOC EXP BIOL 30 0892-6638 2016/04 [Refereed]
  • Ikuo Tsunoda; Seiichi Omura; Fumitaka Sato; Susumu Kusunoki; Mitsugu Fujita; Ah-Mee Park; Faris Hasanovic; Richard Yanagihara; Satoshi Nagata
    Acta medica Kinki University 41 (2) 37 - 52 0386-6092 2016 [Refereed][Invited]
     
    Zika virus (ZIKV) is an enveloped, positive-sense, single-stranded RNA virus that belongs to the genus Flavivirus, family Flaviviridae, which includes many human and animal pathogens, such as dengue virus (DENV), West Nile virus, and Japanese encephalitis virus. In the original as well as subsequent experimental and clinical reports, ZIKV seems to have moderate neurotropism (in animal models) and neurovirulence (in human fetuses), but no neuroinvasiveness (in human adults). Intrauterine ZIKV infection (viral pathology) has been linked to an increased incidence of microcephaly, while increased Guillain-Barré syndrome (GBS) following ZIKV infection is likely immune-mediated (immunopathology). Clinically, in ZIKV infection, antibodies against other flaviviruses, such as DENV, have been detected; these antibodies can cross-react with ZIKV without ZIKV neutralization. In theory, such non-neutralizing antibodies are generated at the expense of decreased production of neutralizing antibodies ("antigenic sin"), leading to poor viral clearance, while the non-neutralizing antibodies can also enhance viral replication in Fc receptor (FcR)-bearing cells via antibody-dependent enhancement (ADE). Here, we propose three potential roles of the antibody-mediated pathogenesis of ZIKV infection: 1) cross-reactive antibodies that recognize ZIKV and neural antigens cause GBS; 2) ZIKV-antibody complex is transported transplacentally via neonatal FcR (FcRn), resulting in fetal infection; and 3) ZIKV-antibody complex is taken up at peripheral nerve endings and transported to neurons in the central nervous system (CNS), by which the virus can enter the CNS without crossing the blood-brain barrier.
  • Fumitaka Sato; Nicholas E. Martinez; Elaine Cliburn Stewart; Seiichi Omura; J. Steven Alexander; Ikuo Tsunoda
    BMC NEUROLOGY BIOMED CENTRAL LTD 15 219  1471-2377 2015/10 [Refereed]
     
    Background: Although the precise mechanism of initial lesion development in multiple sclerosis ( MS) remains unclear, two different neuropathological findings have been reported as a potential early pathology of MS: "microglial nodules" and "newly forming lesions", both of which contain neither T cell infiltration nor demyelination. In microglial nodules, damaged axons were associated with a small number of aggregated macrophages/microglia, while oligodendrocyte apoptosis was a characteristic in newly forming lesions. However, is the presence of" microglial nodules" and "oligodendrogliopathy" mutually exclusive? Might these two different observations be the same neuropathology (as proposed by the concept, "preactive lesions"), but interpreted differently based on the different theories of early MS lesion development, using different staining methods? Discussion: Since two studies are looking at two distinct aspects of early MS pathogenesis (one focused on axons and the other on oligodendrocytes), in a sense, one can say that these two studies are complementary. On the other hand, experimentally, Wallerian degeneration (WD) has been demonstrated to induce both microglial nodules and oligodendrocyte apoptosis in the central nervous system (CNS). Here, when encephalitogenic T cells are present in the periphery in both autoimmune and viral models of MS, induction of WD in the CNS has been shown to result in the recruitment of T cells along the degenerated tract, leading to demyelination (Inside-Out model). These experimental findings are consistent with early MS pathology described by both "microglial nodules" and "newly forming lesions". Conclusions: The differences between the two neuropathological findings may be based on the preference of staining methods, where one group observed axonal and microglial pathology and the other observed oligodendrocyte apoptosis; a Janus face that is looked at from the two different sides.
  • J. S. Alexander; R. Chervenak; B. Weinstock-Guainan; I. Tsunoda; M. Ramanathan; N. Martinez; S. Omura; F. Sato; G. V. Chaitanya; A. Minagar; J. McGee; M. H. Jennings; C. Monceaux; F. Becker; U. Cvek; M. Trutschl; R. Zivadinov
    JOURNAL OF THE NEUROLOGICAL SCIENCES ELSEVIER SCIENCE BV 355 (1-2) 84 - 89 0022-510X 2015/08 [Refereed]
     
    Background: Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as 'microparticles' into the circulation. Objective: To investigate the relationships between these endothelial biomarkers and MS. Methods: We examined the relative abundance of CD31(+)/PECAM-1, CD51(+)CD61(+) (alpha V-3) and CD54(+) (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different micropartide species in MS with conventional MRI (12- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. Results: Differences in circulating micropartide levels were found among MS groups, and several microparticle species (CD31(+)/CD51(+)/CD61(+)/CD54(+)) were found to correlate with conventional MRI and SWI features of MS. Conclusion: These results indicate that circulating microparticles' profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses. (C) 2015 Elsevier B.V. All rights reserved.
  • Felix Becker; Sergey Potepalov; Romana Shehzahdi; Michael Bernas; Marlys Witte; Fleurette Abreo; James Traylor; Wayne A. Orr; Ikuo Tsunoda; Jonathan Steven Alexander
    INFLAMMATORY BOWEL DISEASES LIPPINCOTT WILLIAMS & WILKINS 21 (6) 1282 - 1296 1078-0998 2015/06 [Refereed]
     
    Background:Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2((+/-)) mice would influence the course of disease in a model of experimental colitis.Methods:Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2((+/-)) mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density.Results:We found that FoxC2 downregulation in FoxC2((+/-)) mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature.Conclusions:These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease.
  • Mahmoud Al-Kofahi; Felix Becker; Yuping Wang; Ikuo Tsunoda; Matthew Woolard; Paul A. Jordan; Moheb Boktor; Jonathan S. Alexander
    GASTROENTEROLOGY W B SAUNDERS CO-ELSEVIER INC 148 (4) S693 - S693 0016-5085 2015/04 [Refereed]
  • Felix Becker; Marlys Witte; Moheb Boktor; Ikuo Tsunoda; Paul A. Jordan; Michael Bernas; Fleurette Abreo; Anthony W. Orr; Jonathan S. Alexander
    GASTROENTEROLOGY W B SAUNDERS CO-ELSEVIER INC 148 (4) S721 - S721 0016-5085 2015/04 [Refereed]
  • John E. Greenlee; Susan A. Clawson; Kenneth E. Hill; Blair Wood; Stacey L. Clardy; Ikuo Tsunoda; Noel G. Carlson
    PLOS ONE PUBLIC LIBRARY SCIENCE 10 (4) e0123446  1932-6203 2015/04 [Refereed]
     
    Anti-Yo antibodies are immunoglobulin G (IgG) autoantibodies reactive with a 62 kDa Purkinje cell cytoplasmic protein. These antibodies are closely associated with paraneoplastic cerebellar degeneration in the setting of gynecological and breast malignancies. We have previously demonstrated that incubation of rat cerebellar slice cultures with patient sera and cerebrospinal fluid containing anti-Yo antibodies resulted in Purkinje cell death. The present study addressed three fundamental questions regarding the role of anti-Yo antibodies in disease pathogenesis: 1) Whether the Purkinje cell cytotoxicity required binding of anti-Yo antibody to its intraneuronal 62 kDa target antigen; 2) whether Purkinje cell death might be initiated by antibody-dependent cellular cytotoxicity rather than intracellular antibody binding; and 3) whether Purkinje cell death might simply be a more general result of intracellular antibody accumulation, rather than of specific antibody-antigen interaction. In our study, incubation of rat cerebellar slice cultures with anti-Yo IgG resulted in intracellular antibody binding, and cell death. Infiltration of the Purkinje cell layer by cells of macrophage/microglia lineage was not observed until extensive cell death was already present. Adsorption of anti-Yo IgG with its 62 kDa target antigen abolished both antibody accumulation and cytotoxicity. Antibodies to other intracellular Purkinje cell proteins were also taken up by Purkinje cells and accumulated intracellularly; these included calbindin, calmodulin, PCP-2, and patient anti-Purkinje cell antibodies not reactive with the 62 kDa Yo antigen. However, intracellular accumulation of these antibodies did not affect Purkinje cell viability. The present study is the first to demonstrate that anti-Yo antibodies cause Purkinje cell death by binding to the intracellular 62 kDa Yo antigen. Anti-Yo antibody cytotoxicity did not involve other antibodies or factors present in patient serum and was not initiated by brain mononuclear cells. Purkinje cell death was not simply due to intraneuronal antibody accumulation.
  • Nicholas E. Martinez; Fumitaka Sato; Eiichiro Kawai; Seiichi Omura; Satoru Takahashi; Keigyou Yoh; Ikuo Tsunoda
    BRAIN BEHAVIOR AND IMMUNITY ACADEMIC PRESS INC ELSEVIER SCIENCE 43 86 - 97 0889-1591 2015/01 [Refereed]
     
    In a viral model for multiple sclerosis (MS), Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), both immune-mediated tissue damage (immunopathology) and virus persistence have been shown to cause pathology. T helper (Th) 17 cells are a Th cell subset, whose differentiation requires the transcription factor retinoic acid-related orphan receptor (ROR) gamma t, secrete pro-inflammatory cytokines, including IL-17, and can antagonize Th1 cells. Although Th17 cells have been shown to play a pathogenic role in immune-mediated diseases or a protective role in bacterial and fungal infections, their role in viral infections is unclear. Using newly established Th17-biased ROR gamma t Tg mice, we tested whether Th17 cells could play a pathogenic or protective role in TMEV-IDD by contributing to immunopathology and/or by modulating anti-viral Th1 immune responses. While TMEV-infected wild-type littermate C57BL/6 mice are resistant to TMEV-IDD, ROR gamma t Tg mice developed inflammatory demyelinating lesions with virus persistence in the spinal cord. TMEV-infected ROR gamma t Tg mice had higher levels of IL-17, lower levels of interferon-gamma, and fewer CD8(+) T cells, without alteration in overall levels of anti-viral lymphoproliferative and antibody responses, compared with TMEV-infected wild-type mice. This suggests that a Th17-biased "gain-of-function" mutation could increase susceptibility to virus-mediated demyelinating diseases. (C) 2014 Elsevier Inc. All rights reserved.
  • Eiichiro Kawai; Fumitaka Sato; Seiichi Omura; Nicholas E. Martinez; Pratap C. Reddy; Masaru Taniguchi; Ikuo Tsunoda
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 278 174 - 184 0165-5728 2015/01 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) can induce demyelination or myocarditis insusceptible mouse strains. A deficiency of NKT cells exacerbated TMEV-induced demyelinating disease (TMEV-IDD) in SJL/J and BALB/c mice. In C579L/6 background, however, NKT-cell-deficient J alpha 18 KO mice remained as resistant to TMEV-IDD as wild-type mice. Echocardiography and histology showed that J alpha 18 KO mice developed more severe myocarditis (greater T cell infiltration and fibrosis) than wild-type mice, suggesting a protective role of NKT cells in myocarditis in C57BL/6 mice. J alpha 18 KO mice had higher cardiac viral RNA and anti-viral antibody titers, but had lower lymphoproliferation and IL-4 and IL-10 production. (C) 2014 Elsevier B.V. All rights reserved.
  • Nicholas E. Martinez; Fumitaka Sato; Seiichi Omura; Eiichiro Kawai; Satoru Takahashi; Keigyou Yoh; Ikuo Tsunoda
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 276 (1-2) 142 - 149 0165-5728 2014/11 [Refereed]
     
    Th17 cells play an important role in multiple sclerosis (MS) and its autoimmune model, experimental autoimmune encephalomyelitis (EAE). However, studies have not addressed how enhanced Th17 immune responses can affect demyelinating diseases. We induced EAE with MOG in ROR gamma t transgenic C57BL/6 mice that overexpress a Th17 inducing transcription factor. ROR gamma t transgenic mice developed more severe EAE than wild-type mice with more robust anti-MOG Th17 immune responses. In contrast, mice overexpressing T-bet, a Th1-inducing transcription factor, were resistant to EAE. Therefore, a genetic bias toward Th17 immune responses could contribute to CNS immunopathology. (C) 2014 Elsevier B.V. All rights reserved.
  • Fumitaka Sato; Seiichi Omura; Eiichiro Kawai; Nicholas E. Martinez; Madan M. Acharya; Pratap C. Reddy; Ganta V. Chaitanya; J. Steven Alexander; Ikuo Tsunoda
    CELLULAR IMMUNOLOGY ACADEMIC PRESS INC ELSEVIER SCIENCE 292 (1-2) 85 - 93 0008-8749 2014/11 [Refereed]
     
    We established a novel model of myocarditis induced with Theiler's murine encephalomyelitis virus (TMEV), which has been used as a viral model for multiple sclerosis and seizure/epilepsy. Following TMEV infection, C3H mice developed severe myocarditis with T cell infiltration, while C57BL/6 mice had mild lesions and SJL/J mice had no inflammation in the heart. In C3H mice, myocarditis was divided into three phases: acute viral, subacute immune, and chronic fibrotic phases. Using toll-like receptor (TLR) 4-deficient C3H mice, we found that interleukin (IL)-6, IL-17, TLR4, and anti-viral immune responses were associated with myocarditis susceptibility. (C) 2014 Elsevier Inc. All rights reserved.
  • Greenlee, John E.; Clardy, Stacey L.; Clawson, Susan A.; Wood, Blair; Hill, Kenneth E.; Tsunoda, Ikuo; Carlson, Noel G.
    Annals of Neurology WILEY-BLACKWELL 76 S78 - S78 0364-5134 2014/10 [Refereed]
  • Nicholas E. Martinez; Fridrik Karlsson; Fumitaka Sato; Eiichiro Kawai; Seiichi Omura; Alireza Minagar; Matthew B. Grisham; Ikuo Tsunoda
    BRAIN PATHOLOGY WILEY-BLACKWELL 24 (5) 436 - 451 1015-6305 2014/09 [Refereed]
     
    Multiple sclerosis (MS) has been proposed to be an immune-mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune-mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune-mediated diseases, including MS. However, in virus-induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune-mediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV-infected mice with ex vivo generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin-10 production from B cells, CD4(+) T cells and dendritic cells, which may contribute to the decreased CNS inflammation.
  • John E. Greenlee; Susan A. Clawson; Kenneth E. Hill; Blair Wood; Stacey L. Clardy; Ikuo Tsunoda; Troy D. Jaskowski; Noel G. Carlson
    JOURNAL OF NEUROINFLAMMATION BIOMED CENTRAL LTD 11 160  1742-2094 2014/09 [Refereed]
     
    Background: Anti-Hu and anti-Ri antibodies are paraneoplastic immunoglobulin (Ig)G autoantibodies which recognize cytoplasmic and nuclear antigens present in all neurons. Although both antibodies produce similar immunohistological labeling, they recognize different neuronal proteins. Both antibodies are associated with syndromes of central nervous system dysfunction. However, the neurological deficits associated with anti-Hu antibody are associated with neuronal death and are usually irreversible, whereas neurological deficits in patients with anti-Ri antibody may diminish following tumor removal or immunosuppression. Methods: To study the effect of anti-Hu and anti-Ri antibodies on neurons, we incubated rat hippocampal and cerebellar slice cultures with anti-Hu or anti-Ri sera from multiple patients. Cultures were evaluated in real time for neuronal antibody uptake and during prolonged incubation for neuronal death. To test the specificity of anti-Hu antibody cytotoxic effect, anti-Hu serum IgG was incubated with rat brain slice cultures prior to and after adsorption with its target Hu antigen, HuD. Results: We demonstrated that: 1) both anti-Hu and anti-Ri antibodies were rapidly taken up by neurons throughout both cerebellum and hippocampus; 2) antibody uptake occurred in living neurons and was not an artifact of antibody diffusion into dead cells; 3) intracellular binding of anti-Hu antibody produced neuronal cell death, whereas uptake of anti-Ri antibody did not affect cell viability during the period of study; and 4) adsorption of anti-Hu antisera against HuD greatly reduced intraneuronal IgG accumulation and abolished cytotoxicity, confirming specificity of antibody-mediated neuronal death. Conclusions: Both anti-Hu and anti-Ri antibodies were readily taken up by viable neurons in slice cultures, but the two antibodies differed markedly in terms of their effects on neuronal viability. The ability of anti-Hu antibodies to cause neuronal death could account for the irreversible nature of paraneoplastic neurological deficits in patients with this antibody response. Our results raise questions as to whether anti-Ri antibody might initially induce reversible neuronal dysfunction, rather than causing cell death. The ability of IgG antibodies to access and react with intracellular neuronal proteins could have implications for other autoimmune diseases involving the central nervous system.
  • Seiichi Omura; Eiichiro Kawai; Fumitaka Sato; Nicholas E. Martinez; Ganta V. Chaitanya; Phoebe A. Rollyson; Urska Cvek; Marjan Trutschl; J. Steven Alexander; Ikuo Tsunoda
    CIRCULATION-CARDIOVASCULAR GENETICS LIPPINCOTT WILLIAMS & WILKINS 7 (4) 444 - 454 1942-325X 2014/08 [Refereed]
     
    Background-Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler's murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. Methods and Results-Using this novel model for viral myocarditis induced with Theiler's murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler's murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity-related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity-related genes, such as Cd3g and H2-Aa; and cardiac remodeling-related genes, such as Mmp12 and Gpnmb. Conclusions-Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.
  • Mahmoud Al-Kofahi; Judith L. Palmer Castor; Matthew Woolard; Ikuo Tsunoda; Yuping Wang; Moheb Boktor; Paul A. Jordan; Ankur Sheth; David C. Zawieja; Mariappan Muthuchamy; Pierre-Yves von der Weid; Dmitry Ostanin; Kavya Pinto; Felix Becker
    GASTROENTEROLOGY W B SAUNDERS CO-ELSEVIER INC 146 (5) S830 - S830 0016-5085 2014/05 [Refereed]
  • Fereidoon Shafiei; Seiichi Omura; Eiichiro Kawai; Fumitaka Sato; Nicholas E. Martinez; Viromi Fernando; Liam Morris; J. Steven Lexander; Urska Cvek; Marjan Trutschl; Ikuo Tsunoda
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY ELSEVIER SCIENCE INC 63 (12) A971 - A971 0735-1097 2014/04 [Refereed]
  • Viromi Fernando; Seiichi Omura; Fumitaka Sato; Eiichiro Kawai; Nicholas E. Martinez; Sadie Faith Elliott; Keigyou Yoh; Satoru Takahashi; Ikuo Tsunoda
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES MDPI AG 15 (2) 1700 - 1718 1422-0067 2014/02 [Refereed]
     
    T helper (Th)2 cells have been proposed to play a neuroprotective role in multiple sclerosis (MS). This is mainly based on loss-of-function studies in an animal model for MS, experimental autoimmune encephalomyelitis (EAE), using blocking antibodies against Th2 related cytokines, and knockout mice lacking Th2-related molecules. We tested whether an increase of Th2 responses (gain-of-function approach) could alter EAE, the approach of novel GATA binding protein 3 (GATA3)-transgenic (tg) mice that overexpress GATA3, a transcription factor required for Th2 differentiation. In EAE induced with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide, GATA3-tg mice had a significantly delayed onset of disease and a less severe maximum clinical score, compared with wild-type C57BL/6 mice. Histologically, GATA3-tg mice had decreased levels of meningitis and demyelination in the spinal cord, and anti-inflammatory cytokine profiles immunologically, however both groups developed similar levels of MOG-specific lymphoproliferative responses. During the early stage, we detected higher levels of interleukin (IL)-4 and IL-10, with MOG and mitogen stimulation of regional lymph node cells in GATA3-tg mice. During the late stage, only mitogen stimulation induced higher IL-4 and lower interferon- and IL-17 production in GATA3-tg mice. These results suggest that a preexisting bias toward a Th2 immune response may reduce the severity of inflammatory demyelinating diseases, including MS.
  • Fumitaka Sato; Nicholas E. Martinez; Maira Shahid; John W. Rose; Noel G. Carlson; Ikuo Tsunoda
    AMERICAN JOURNAL OF PATHOLOGY ELSEVIER SCIENCE INC 183 (5) 1390 - 1396 0002-9440 2013/11 [Refereed]
     
    The polyphenol compound resveratrol is reported to have multiple functions, including neuroprotection, and no major adverse effects have been reported. Although the neuroprotective effects have been associated with sirtuin 1 activation by resveratrol, the mechanisms by which resveratrol exerts such functions are a matter of controversy. We examined whether resveratrol can be neuroprotective in two models of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). EAE was induced in C57BL/6 mice, which were fed a control diet or a diet containing resveratrol during either the induction or effector phase or through the whole course of EAE. SJL/J mice were infected with TMEV and fed a control diet or a diet containing resveratrol during the chronic phase of TMEV-IDD. In EAE, all groups of mice treated with resveratrol had more severe clinical signs than the control group. In particular, resveratrol treatment during the induction phase resulted in the most severe EAE, both clinically and histologically. Similarly, in the viral model, the mice treated with resveratrol developed significantly more severe TMEV-IDD than the control group. Thus, surprisingly, the resveratrol treatment significantly exacerbated demyelination and inflammation without neuroprotection in the central nervous system in both models. Our findings indicate that caution should be exercised in potential therapeutic applications of resveratrol in human inflammatory demyelinating diseases, including multiple sclerosis.
  • Fridrik Karlsson; Nicholas E. Martinez; Laura Gray; Songlin Zhang; Ikuo Tsunoda; Matthew B. Grisham
    INFLAMMATORY BOWEL DISEASES LIPPINCOTT WILLIAMS & WILKINS 19 (11) 2282 - 2294 1078-0998 2013/10 [Refereed]
     
    The objectives of this study were to (a) evaluate and compare the ability of ex vivo-generated induced regulatory T cells (iTregs) and freshly isolated natural Tregs (nTregs) to reverse/attenuate preexisting intestinal inflammation in a mouse model of chronic colitis and (b) quantify the Treg-targeted gene expression profiles of these two Treg populations. We found that ex vivo-generated iTregs were significantly more potent than nTregs at attenuating preexisting colitis. This superior therapeutic activity was associated with increased accumulation of iTregs within the mesenteric lymph nodes and large and significant reductions in interleukin (IL)-6 and IL-17A expression in the colons of iTreg- versus nTreg-treated mice. The enhanced immunosuppressive activity of iTregs was not because of increased expression or stability of Foxp3 as iTregs and nTregs obtained from the mesenteric lymph nodes, and colons of reconstituted mice expressed similar levels of this important transcription factor. In addition, we observed a total of 27 genes that were either upregulated or downregulated in iTregs when compared with nTregs. Although iTregs were found to be superior at reversing established disease, their message levels of IL-10 and IL-35 and surface expression of the gut-homing molecules CCR9 and (47) were significantly reduced when compared with nTregs. Taken together, our data demonstrate that ex vivo-generated iTregs are significantly more potent than nTregs at attenuating preexisting gut inflammation despite reduced expression of classical regulatory cytokines and gut-homing molecules. Our data suggest that the immunosuppressive activity of iTregs may be because of their ability to directly or indirectly decrease expression of IL-6 and IL-17A within the inflamed bowel.
  • Ganta Vijay Chaitanya; Seiichi Omura; Fumitaka Sato; Nicholas E. Martinez; Alireza Minagar; Murali Ramanathan; Bianca Weinstock Guttman; Robert Zivadinov; Ikuo Tsunoda; Jonathan S. Alexander
    JOURNAL OF NEUROINFLAMMATION BIOMED CENTRAL LTD 10 125  1742-2094 2013/10 [Refereed]
     
    Background: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin(+) (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. Methods: We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature. Results and conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
  • Alexander, J. S.; Prouty, L.; Tsunoda, I.; Ganta, C. V.; Minagar, A.
    Bmc Medicine BIOMED CENTRAL LTD 11 14 - 14 1741-7015 2013/10 [Refereed]
     
    The role of the venous system in the pathogenesis of inflammatory neurological/neurodegenerative diseases remains largely unknown and underinvestigated. Aside from cerebral venous infarcts, thromboembolic events, and cerebrovascular bleeding, several inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and optic neuritis, appear to be associated with venous vascular dysfunction, and the neuropathologic hallmark of these diseases is a perivenous, rather than arterial, lesion. Such findings raise fundamental questions about the nature of these diseases, such as the reasons why their pathognomonic lesions do not develop around the arteries and what exactly are the roles of cerebral venous inflammation in their pathogenesis. Apart from this inflammatory-based view, a new hypothesis with more focus on the hemodynamic features of the cerebral and extracerebral venous system suggests that MS pathophysiology might be associated with the venous system that drains the CNS. Such a hypothesis, if proven correct, opens new therapeutic windows in MS and other neuroinflammatory diseases. Here, we present a comprehensive review of the pathophysiology of MS, ADEM, pseudotumor cerebri, and optic neuritis, with an emphasis on the roles of venous vascular system programming and dysfunction in their pathogenesis. We consider the fundamental differences between arterial and venous endothelium, their dissimilar responses to inflammation, and the potential theoretical contributions of venous insufficiency in the pathogenesis of neurovascular diseases.
  • Ikuo Tsunoda
    Circulation Research LIPPINCOTT WILLIAMS & WILKINS 113 (4) 0009-7330 2013/08 [Refereed]
  • Greenlee John; Clawson Susan; Wood Blair; Hill Kenneth; Tsunoda Ikuo; Carlson Noel
    NEUROLOGY 80 0028-3878 2013/02 [Refereed]
  • Jane E. Libbey; Ikuo Tsunoda; Robert S. Fujinami
    JOURNAL OF NEUROVIROLOGY SPRINGER 18 (6) 471 - 478 1355-0284 2012/12 [Refereed]
     
    No one single pathogen has been identified as the causative agent of multiple sclerosis (MS). Alternately, the likelihood of an autoimmune event may be nonspecifically enhanced by different infectious agents. In a novel animal model of MS, SJL/J mice primed through infection with a recombinant vaccinia virus (VV) encoding myelin proteolipid protein (PLP) (VVPLP) were susceptible to a central nervous system (CNS) inflammatory disease following administration of a nonspecific immunostimulant [complete Freund's adjuvant (CFA) plus Bordetella pertussis (BP)]. Mononuclear cells isolated from the brains, but not the spleens, of VVPLP-primed CFA/BP challenged mice produced interleukin (IL)-17 and interferon-gamma and transferred a CNS inflammatory disease to na < ve SJL/J mice. Administration of curdlan, a T helper 17 cell inducer, unexpectedly resulted in less severe clinical and histological signs of disease, compared to CFA/BP challenged mice, despite the induction of IL-17 in the periphery. Further examination of the VVPLP-prime CFA/BP challenge model may suggest new mechanisms for how different pathogens associated with MS can protect or enhance disease.
  • Nicholas E. Martinez; Fumitaka Sato; Seiichi Omura; Eiichiro Kawai; Satoru Takahashi; Keigyou Yoh; Ikuo Tsunoda
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 253 (1-2) 105 - 106 0165-5728 2012/12 [Refereed]
  • Fumitaka Sato; Seiichi Omura; Nicholas E. Martinez; Eiichiro Kawai; Ganta V. Chaitanya; Jonathan S. Alexander; Ikuo Tsunoda
    CIRCULATION RESEARCH LIPPINCOTT WILLIAMS & WILKINS 111 (4) 0009-7330 2012/08 [Refereed]
  • Eiichiro Kawai; Seiichi Omura; Fumitaka Sato; Nicholas E. Martinez; Ganta V. Chaitanya; William C. Claycomb; J. S. Alexander; Ikuo Tsunoda
    CIRCULATION RESEARCH LIPPINCOTT WILLIAMS & WILKINS 111 (4) 0009-7330 2012/08 [Refereed]
  • Nicholas E. Martinez; Fumitaka Sato; Eiichiro Kawai; Seiichi Omura; Robert P. Chervenak; Ikuo Tsunoda
    FUTURE VIROLOGY FUTURE MEDICINE LTD 7 (6) 593 - 608 1746-0794 2012/06 [Refereed]
     
    In immune-mediated diseases, Treg and proinflammatory Th17 cells have been suggested to play either suppressor (beneficial) or effector (detrimental) roles, respectively. Tissue damage in viral infections can be caused by direct viral replication or immunopathology. Viral replication can be enhanced by anti-inflammatory responses and suppressed by proinflammatory responses. However, Tregs could suppress proinflammatory responses, reducing immunopathology, while Th17 cell-induced inflammation may enhance immunopathology. Here, the roles of Treg and Th17 cells depend on whether tissue damage is caused by direct virus replication or immunopathology, which differ depending on the virus, disease stage and host immune background. Although the precise mechanisms of tissue damage in multiple sclerosis and myocarditis are unclear, both viral replication and immune effector cells have been proposed to cause pathogenesis. Personalized medicine that alters the balance between Treg and Th17 cells may ameliorate viral pathology during infections.
  • Martinez NE; Sato F; Omura S; Minagar A; Alexander JS; Tsunoda I
    Pathophysiology : the official journal of the International Society for Pathophysiology / ISP 20 (1) 71 - 84 0928-4680 2012/05 [Refereed]
     
    Multiple sclerosis (MS) is a disease which can presents in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose '1-stage' and '2-stage' disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the '1-stage disease' theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The '2-stage disease' theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler's virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage.
  • Fumitaka Sato; Nicholas Martinez; Seiichi Omura; Steve Alexander; Alireza Minagar; Ikuo Tsunoda
    NEUROLOGY LIPPINCOTT WILLIAMS & WILKINS 78 0028-3878 2012/04 [Refereed]
  • Ikuo Tsunoda; Jane E. Libbey; Robert S. Fujinami
    JOURNAL OF NEUROVIROLOGY SPRINGER 18 (2) 127 - 137 1355-0284 2012/04 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) causes a demyelinating disease similar to multiple sclerosis in the central nervous system (CNS) of susceptible SJL/J mice. Immune responses to TMEV contribute to viral clearance as well as to demyelination. We constructed recombinant vaccinia viruses (VV) that encode each or all of the capsid proteins (VVVP1, VVVP2, VVVP3, VVVP4, and VVall) or non-structural proteins (VVP2, VVP2P3, and VV3'P3) of the Daniels strain of TMEV. To determine the role of each of the coding regions of TMEV in vivo, we immunized SJL/J mice with each recombinant VV, with or without subsequent TMEV infection. The groups of mice were compared clinically, immunologically, and histologically. No mice immunized with any recombinant VV without subsequent TMEV infection developed demyelination. However, antibody responses to TMEV were detected in mice immunized with VVall. In addition, in some mice, VVP2 immunization induced mild meningitis. VVVP3 or VVVP4 immunization of mice prior to TMEV infection ameliorated TMEV-induced pathology or clinical signs of disease. The beneficial effect of VP4 immunization was also seen through DNA immunization with a plasmid encoding VP4 and leader prior to TMEV infection. Therefore, vaccination against not only surface capsid proteins (VVVP3 and VVall) but also non-surface capsid protein (VVVP4), and non-structural proteins (VVP2) can elicit immune responses to virus or modulate subsequent viral-induced CNS disease.
  • Nicholas E. Martinez; Fridrik Karlsson; Fumitaka Sato; Seiichi Omura; Alireza Minagar; Mathew B. Grisham; Ikuo Tsunoda
    ANNALS OF NEUROLOGY WILEY-BLACKWELL 70 S90 - S91 0364-5134 2011/10 [Refereed]
  • Fumitaka Sato; Nicholas E. Martinez; Seiichi Omura; Ikuo Tsunoda
    EXPERT REVIEW OF CLINICAL IMMUNOLOGY EXPERT REVIEWS 7 (2) 165 - 167 1744-666X 2011/03 [Refereed]
     
    The 10th International Congress of Neuroimmunology, including the 10th European School of Neuroimmunology Course, was held by the International Society of Neuroimmunology in Sitges (Barcelona, Spain) on 26-30 October 2010. The conference covered a wide spectrum of issues and challenges in both basic science and clinical aspects of neuroimmunology. Data and ideas were shared through a variety of programs, including review talks and poster sessions. One of the topics of the congress was whether multiple sclerosis is a homogenous or heterogenous disease, clinically and pathologically, throughout its course.
  • Seiichi Omura; Fumitaka Sato; Nicholas E. Martinez; Nikki J. Kennett; Ikuo Tsunoda
    NEUROLOGY LIPPINCOTT WILLIAMS & WILKINS 76 (9) A460 - A460 0028-3878 2011/03 [Refereed]
  • Sato F; Tanaka H; Hasanovic F; Tsunoda I
    Pathophysiology : the official journal of the International Society for Pathophysiology / ISP 1 18 (1) 31 - 41 0928-4680 2011/02 [Refereed]
  • Sato Fumitaka; Martinez Nicholas; Rose John; Carlson Noel; Tsunoda Ikuo
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 228 (1-2) 95 - 96 0165-5728 2010/11 [Refereed]
  • Greenlee E. John; Clawson A. Susan; Hill E. Kenneth; Wood L. Blair; Ikuo Tsunoda; Carlson G. Noel
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 228 (1-2) 189 - 189 0165-5728 2010/11 [Refereed]
  • John E. Greenlee; Susan A. Clawson; Kenneth E. Hill; Blair L. Wood; Ikuo Tsunoda; Noel G. Carlson
    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LIPPINCOTT WILLIAMS & WILKINS 69 (10) 997 - 1007 0022-3069 2010/10 [Refereed]
     
    Paraneoplastic cerebellar degeneration accompanying gynecological and breast cancers is characteristically accompanied by a serum and cerebrospinal fluid (CSF) antibody response, termed "anti-Yo" which reacts with cytoplasmic proteins of cerebellar Purkinje cells. Because these antibodies interact with cytoplasmic rather than cell surface membrane proteins, their role in causing Purkinje cell death has been questioned. To address this issue, we studied the interaction of anti-Yo antibodies with Purkinje cells in slice (organotypic) cultures of rat cerebellum. We incubated cultures with immunoglobulin G (IgG)-containing anti-Yo antibodies using titers of anti-Yo antibody equivalent to those found in CSF of affected patients. Cultures were then studied in real time and after fixation for potential uptake of antibody and induction of cell death. Anti-Yo antibodies delivered in serum, CSF, or purified IgG were taken up by viable Purkinje cells, accumulated intracellularly, and were associated with cell death. Normal IgG was also taken up by Purkinje cells but did not accumulate and did not affect cell viability. These findings indicate that autoantibodies directed against intracellular Purkinje cell proteins can be taken up to cause cell death and suggest that anti-Yo antibody may be directly involved in the pathogenesis of paraneoplastic cerebellar degeneration.
  • Ikuo Tsunoda; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNE PHARMACOLOGY SPRINGER 5 (3) 355 - 369 1557-1890 2010/09 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS). TMEV induces a biphasic disease in susceptible mouse strains. During the acute phase, 1 week after infection, TMEV causes polioencephalomyelitis characterized by infection and apoptosis of neurons in the gray matter of the brain. During the chronic phase, about 1 month after infection, virus infects glial cells and macrophages, and induces inflammatory demyelination with oligodendrocyte apoptosis and axonal degeneration in the white matter of the spinal cord. Although antibody, CD4(+), and CD8(+) T cell responses against TMEV capsid proteins play important roles in neuropathogenesis, infectious virus with persistence is necessary to induce demyelination; in general, adoptive transfer of antibody or T cells alone did not induce central nervous system (CNS) disease. The TMEV model can be useful for testing new therapeutic strategies specifically as a viral model for MS. Therapies targeting adhesion molecules, axonal degeneration, and immunosuppression can be beneficial for pure autoimmune CNS demyelinating diseases, such as experimental autoimmune encephalomyelitis, but could be detrimental in virus-induced demyelinating diseases, such as progressive multifocal leukoencephalopathy.
  • Jane E. Libbey; Ikuo Tsunoda; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNE PHARMACOLOGY SPRINGER 5 (2) 168 - 175 1557-1890 2010/06 [Refereed]
     
    Experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis, can be induced through inoculation with several different central nervous system (CNS) proteins or peptides. Modulation of EAE, resulting in either protection from EAE or enhancement of EAE, can also be accomplished through either vaccination or DNA immunization with molecular mimics of self-CNS proteins. Previously published data on this method of EAE modulation will be reviewed. New data is presented, which demonstrates that EAE can also be modulated through the administration of the beta-(1,3)-d-glucan, curdlan. Dendritic cells stimulated by curdlan are involved in the differentiation of the interleukin-17 producing subset of CD4(+) T cells that are recognized effector cells in EAE. Using two different systems to study the effects of curdlan on EAE, it was found that curdlan increased the incidence of EAE and/or the severity of the disease course.
  • Fumitaka Sato; John W. Rose; Noel G. Carlson; Alireza Minagar; Ikuo Tsunoda
    NEUROLOGY LIPPINCOTT WILLIAMS & WILKINS 74 (9) A561 - A561 0028-3878 2010/03 [Refereed]
  • Robert S. Fujinami; Ikuo Tsunoda
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 15 29 - 30 1355-0284 2009 [Refereed]
  • Ikuo Tsunoda; Noel G. Carlson; Blair L. Wood; Faris Hasanovic; John W. Rose
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 15 100 - 100 1355-0284 2009 [Refereed]
  • Davis JR; Giles AC; Rankin CH; Bell J; Kimura H; Uemura T; Kidokoro Y; Lemieux M; Koninck PD; Carbone E; Senatore A; Spafford JD; Dowie MJ; dummy-AUTHOR_name; Biel M
    Encyclopedia of Neuroscience 2009/01
  • Ikuo Tsunoda; Tomoko Tanaka; Masaru Taniguchi; Robert S. Fujinami
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 15 (1) 90 - 98 1355-0284 2009 [Refereed]
     
    Most natural killer (NK) T cells express an invariant V14 T-cell receptor. To explore the contribution of NKT cells in an animal model for multiple sclerosis, Theiler's murine encephalomyelitis virus (TMEV) infection, TMEV-infected mice were treated with V14 antibody. Treatment during the early stage of infection delayed the onset of demyelinating disease with higher interleukin-4 production, whereas administration during the late stage or weekly resulted in more severe demyelination with enhanced virus persistence. The effect of in vivo depletion of NKT cells differed depending on the stage of infection, suggesting contrasting roles for NKT cells over the disease course.
  • Ikuo Tsunoda; Jane E. Libbey; Robert S. Fujinami
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 15 (1) 81 - 89 1355-0284 2009 [Refereed]
     
    DA and GDVII are strains of Theiler's murine encephalomyelitis virus (TMEV). DA virus mutant DApB encodes VP2 puff B of GDVII, whereas DApBL2M contains VP1 loop II of GDVII with a point mutation in VP2 puff B. Neuraminidase treatment of cells inhibited infection by DA and DApB, but not GDVII or DApBL2M viruses; sialic acid (SA) binding correlated with virus persistence. In virus binding assays to intestine sections, all four TMEVs bound goblet cells and the mucus of the epithelium that was SA dependent. Therefore, differences in SA composition on different cell types can affect tropism and infection.
  • W. Todd Penberthy; Ikuo Tsunoda
    CURRENT PHARMACEUTICAL DESIGN BENTHAM SCIENCE PUBL LTD 15 (1) 64 - 99 1381-6128 2009/01 [Refereed][Invited]
     
    The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld(S) mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld(S) genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NAD-complementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.
  • Diethilde J. Theil; Jane E. Libbey; Fernando Rodriguez; J. Lindsay Whitton; Ikuo Tsunoda; Tobias J. Derfuss; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 204 (1-2) 92 - 100 0165-5728 2008/11 [Refereed]
     
    Relapsing-remitting experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model, is induced in mice by injection of myelin proteolipid protein (PLP) encephalitogenic peptide, PLP(139-151), in adjuvant. In this study, prior to EAE induction, mice were vaccinated with a bacterial plasmid encoding a PLP-ubiquitin fusion (pCMVUPLP). During the relapse phase of EAE, clinical signs, histopathologic changes, in vitro lymphoproliferation to PLP(139-151) and interferon-gamma levels were reduced in pCMVUPLP-vaccinated mice, compared to mock-vaccinated mice (controls). Lymphocytes from pCMVUPLP-vaccinated mice produced interleukin-4, a cytokine lacking in controls. Thus, pCMVUPLP vaccination can modulate the relapse after EAE induction. (C) 2008 Elsevier BY. All rights reserved.
  • Ikuo Tsunoda
    FUTURE VIROLOGY FUTURE MEDICINE LTD 3 (6) 579 - 593 1746-0794 2008/11 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) and other neurotropic virus infections result in degeneration of each component of the neuron: apoptosis of the cell body, axonal (Wallerian) degeneration, and dendritic and synaptic pathology. In general, axonal degeneration is detrimental for hosts. However, axonal degeneration can be beneficial in the case of infection with neurotropic viruses that spread in the CNS using axonal transport, C57BL/Wld(s) (WId(s), Wallerian degeneration slow mutant) mice are protected from axonal degeneration. WIds mice infected with the neurovirulent GDVII strain of TMEV are more resistant to virus infection than wild-type mice, suggesting that axonal preservation contributes to the resistance. By contrast, infection with the less virulent Daniels strain of TMEV results in high levels of virus propagation in the CNS, suggesting that prolonged survival of axons in WIds mice favors virus spread. Thus, axonal degeneration might be a beneficial self-destruct mechanism that limits the spread of neurotropic viruses, in the case of less virulent virus infection. We hypothesize that neurons use 'built-in' self-destruct protection machinery (compartmental neurodegeneration) against neurotropic virus infection, since the CNS is an immunologically privileged site. Early induction of apoptosis in the neuronal cell body limits virus replication. Wallerian degeneration of the axon prevents axonal transport of virus. Dendritic and synaptic degeneration blocks virus transmission at synapses. Thus, the balance between neurodegeneration and virus propagation may be taken into account in the future design of neuroprotective therapy.
  • Ikuo Tsunoda; John W. Rose; Monica Rojas; Faris Hasanovic; Noel G. Carlson
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 203 (2) 247 - 247 0165-5728 2008/10 [Refereed]
  • Ikuo Tsunoda; Tomoko Tanaka; Robert S. Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 82 (20) 10279 - 10289 0022-538X 2008/10 [Refereed]
     
    The GDVII strain of Theiler's murine encephalomyelitis virus ( TMEV) causes an acute fatal polioencephalomyelitis in mice. Infection of susceptible mice with the DA strain of TMEV results in an acute polioencephalomyelitis followed by chronic immune-mediated demyelination with virus persistence in the central nervous system (CNS); DA virus infection is used as an animal model for multiple sclerosis. CD1d-restricted natural killer T (NKT) cells can contribute to viral clearance and regulation of autoimmune responses. To investigate the role of CD1d in TMEV infection, we first infected CD1d-deficient mice (CD1(-/-)) and wild-type BALB/c mice with GDVII virus. Wild-type mice were more resistant to virus than CD1(-/-) mice (50% lethal dose titers: wild-type mice, 10 PFU; CD1(-/-) mice, 1.6 PFU). Wild-type mice had fewer viral antigen-positive cells with greater inflammation in the CNS than CD1(-/-) mice. Second, an analysis of DA virus infection in CD1(-/-) mice was conducted. Although both wild-type and CD1(-/-) mice had similar clinical signs during the first 2 weeks after infection, CD1(-/-) mice had an increase in neurological deficits over those observed in wild-type mice at 3 to 5 weeks after infection. Although wild-type mice had no demyelination, 20 and 60% of CD1(-/-) mice developed demyelination at 3 and 5 weeks after infection, respectively. TMEV-specific lymphoproliferative responses, interleukin-4 (IL-4) production, and IL-4/gamma interferon ratios were higher in CD1(-/-) mice than in wild-type mice. Thus, CD1d-restricted NKT cells may play a protective role in TMEV-induced neurological disease by alteration of the cytokine profile and virus-specific immune responses.
  • Ikuo Tsunoda; Noel G. Carlson; Monica Rojas; Faris Hasanovic; John W. Rose
    MULTIPLE SCLEROSIS SAGE PUBLICATIONS LTD 14 S91 - S91 1352-4585 2008/09 [Refereed]
  • Lisa K. Peterson; Ikuo Tsunoda; Jane E. Libbey; Robert S. Fujinami
    EXPERIMENTAL AND MOLECULAR PATHOLOGY ACADEMIC PRESS INC ELSEVIER SCIENCE 85 (1) 28 - 39 0014-4800 2008/08 [Refereed]
     
    B10.S mice have been considered resistant to experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, sensitization with a myelin oligodendrocyte glycoprotein (MOG) peptide, MOC(92-106), induced clinical signs in 30% of mice and central nervous system (CNS) pathology in 93% of mice. Symptomatic mice had more demyelination, inflammation, perivascular cuffing and axonal damage in the CNS compared to asymptomatic mice, but no strong correlations between CNS pathology and clinical score were found. Interestingly, the ratio of B cells to T cells in cellular infiltrates correlated with clinical score. This suggests that the balance between B and T cells contributes to expression of clinical signs. (c) 2008 Elsevier Inc. All rights reserved.
  • Ikuo Tsunoda; Tomoko Tanaka; Faris Hasanovic; Robert S. Fujinami
    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LIPPINCOTT WILLIAMS & WILKINS 67 (5) 491 - 492 0022-3069 2008/05 [Refereed]
  • Ikuo Tsunoda; Tomoko Tanaka; Faris Hasanovic; Robert S. Fujinami
    FASEB JOURNAL FEDERATION AMER SOC EXP BIOL 22 0892-6638 2008/04 [Refereed]
  • Ikuo Tsunoda; Tomoko Tanaka; Masaru Taniguchi; Faris Hasanovic; Robert Fujinami
    FASEB JOURNAL FEDERATION AMER SOC EXP BIOL 22 0892-6638 2008/04 [Refereed]
  • Lisa K. Peterson; Ikuo Tsunoda; Robert S. Fujinami
    AUTOIMMUNITY INFORMA HEALTHCARE 41 (5) 353 - 362 0891-6934 2008 [Refereed]
     
    Hybridoma cell lines producing natural autoantibodies (NAA), generated from A. SW mice with progressive experimental autoimmune encephalomyelitis (P-EAE), have been shown to cause demyelination and renal pathology when injected into naive mice. To investigate the relative contribution of these antibodies to disease pathogenesis, B-1 cells, the major producers of NAA, were depleted by hypotonic shock. Depletion of B-1 cells during the effector phase of EAE significantly decreased the severity of demyelination and overall pathology in the brain. There was also a decreased incidence of P-EAE and a decrease in clinical score. Depletion during the induction phase of the disease resulted in an increase in the incidence of P-EAE and in the clinical score. Overall, B-1 cells were found to modulate EAE pathogenesis.
  • Lisa K. Peterson; Takahisa Masaki; Steven R. Wheelwright; Ikuo Tsunoda; Robert S. Fujinami
    AUTOIMMUNITY INFORMA HEALTHCARE 41 (7) 526 - 536 0891-6934 2008 [Refereed]
     
    Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model for multiple sclerosis (MS). Previously, we reported renal immunoglobulin (Ig) deposition in mice with myelin oligodendrocyte glycoprotein (MOG(92-106))-induced progressive EAE and naive mice injected with MOG(92-106) hybridoma cells producing antibody that cross-reacts with various autoantigens including double-stranded DNA. To assess whether MOG(92-106) antibodies actually induce kidney changes, the extent of renal Ig deposition and changes in glomerular histology and filtration were investigated. Mice with progressive EAE exhibited Ig deposition, glomerular hypercellularity and proteinuria indicating kidney dysfunction. MOG(92-106) hybridoma cell injected mice also had Ig deposition and proteinuria. Therefore, sensitization with MOG(92-106) and transfer of MOG(92-106) antibodies can induce both central nervous system and renal pathology. The renal involvement reported in MS is believed to occur as a side effect of nephrotoxic drugs or neurogenic bladder. Our results demonstrate that an autoimmune response against myelin could induce pathologic changes in the kidney and may help explain renal changes reported in patients with progressive MS.
  • Ikuo Tsunoda; Tomoko Tanaka; Yukio Saijoh; Robert S. Fujinami
    AMERICAN JOURNAL OF PATHOLOGY AMER SOC INVESTIGATIVE PATHOLOGY, INC 171 (5) 1563 - 1575 0002-9440 2007/11 [Refereed]
     
    In Theiler's murine encephalomyelitis virus (TMEV) infection, an animal model for multiple sclerosis (MS), axonal injury precedes inflammatory demyelinating lesions, and the distribution of axonal damage present during the early phase of infection corresponds to regions where subsequent demyelination occurs during the chronic phase. We hypothesized that axonal damage recruits inflammatory cells to sites of Wallerian degeneration, leading to demyelination. Three weeks after TMEV infection, axonal degeneration was induced in the posterior funiculus of mice by injecting the toxic lectin Ricinus communis agglutinin (RCA) I into the sciatic nerve. Neuropathology was examined I week after lectin injection. Control mice, infected with TMEV but receiving no RCA 1, had inflammatory demyelinating lesions in die anterior/lateral funiculi. Other control mice that received RCA I alone did not develop inflammatory lesions. In contrast, RCA I injection into TMEV-infected mice induced lesions in the posterior funiculus in addition to the anterior/lateral funiculi. We found no differences in lymphoproliferative responses or antibody titers against TMEV among the groups. This suggests that axonal degeneration contributes to the recruitment of inflammatory cells into the central nervous system by altering the local microenvironment. In this scenario, lesions develop from the axon (inside) to the myelin (outside) (inside-Outmodel).
  • Ikuo Tsunoda; Jane E. Libbey; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 190 (1-2) 80 - 89 0165-5728 2007/10 [Refereed]
     
    GDVII and DA strains of Theiler's murine encephalomyelitis virus (TMEV) differ in VP2 puff B. One week after GDVII virus infection, SJL/J mice had large numbers of TUNEL+ apoptotic cells with a relative lack of T cell infiltration in the brain. DA viruses with mutation in puff B induced higher levels of apoptosis than wild-type DA virus, but levels of inflammation in brains were similar between DA and DA virus mutants. The difference in inflammation among TMEVs could be due to TGF-beta 1 expression that was seen only in GDVII virus infection and negatively correlated with CD3(+) T cell infiltration. (C) 2007 Elsevier B.V. All rights reserved.
  • Ikuo Tsunoda; Jane E. Libbey; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 188 (1-2) 22 - 33 0165-5728 2007/08 [Refereed]
     
    VVPLP is a recombinant vaccinia, virus (VV) encoding myelin proteolipid protein (PLP) that has been used to investigate molecular mimicry and amoirrimunity. Since virus infections can cause bystander activation, mice were first infected with VVPLP, and later challenged with wild-type VV, lymphocytic choriomeningitis virus (LCMV), or murine cytornegalovirus (MCMV). Among the VVPLP-primed mice, only MCMV challenge induced significant Ki-67(+), CD3-(+)Tcell infiltration into the central nervous system (CNS) with a mild PLP antibody response. While MCMValone caused no CNS disease, control VV-infected mice followed with MCMV developed mild CNS inflammation. Thus, heterologous virus infections can induce CNS pathology. (c) 2007 Elsevier B.V. All rights reserved.
  • Jane E. Libbey; Ikuo Tsunoda; J. Lindsay Whitton; Robert S. Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 81 (6) 3009 - 3011 0022-538X 2007/03 [Refereed]
     
    The DA strain of Theiler's murine encephalomyelitis virus (TMEV) persistently infects cells of the spinal cord during the chronic phase of infection. Although in situ hybridization and reverse transcription-PCR have demonstrated the presence of vital RNA in the spinal cord, it has not been determined whether this RNA is infectious and, if so, how many PFU equivalents of virus the RNA can yield. In this study, we demonstrated that TMEV RNA isolated from the spinal cords of chronically infected mice is infectious and that there is at least 30-fold more infectious RNA than infectious virus in the spinal cords of these mice.
  • Lisa K. Peterson; Ikuo Tsunoda; Takahisa Masaki; Robert S. Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 183 (1-2) 69 - 80 0165-5728 2007/02 [Refereed]
     
    Two myelin oligodendrocyte glycoprotein (MOG(92-106)) monoclonal antibodies (mAbs) were produced from an A.SW mouse with progressive experimental autoimmune encephalomyelitis. Polyreactivity/specificity of the mAbs was demonstrated by ELISA. Functionality and a potential role in pathogenesis of systemic autoimmunity were demonstrated in vitro in a lymphocytotoxicity assay and in vivo upon injection into naive mice. Injection of MOG mAb producing hybridomas into naive mice resulted in immunoglobulin deposition in kidneys and liver. This model will be useful in determining whether transitional forms between CNS (organ)-specific and systemic autoimmune diseases exist, and whether progressive multiple sclerosis has features of a systemic autoimmune disease. (c) 2006 Elsevier B.V All rights reserved.
  • Ikuo Tsunoda; Tomoko Tanaka; Emily Jane Terry; Robert S. Fujinami
    AMERICAN JOURNAL OF PATHOLOGY AMER SOC INVESTIGATIVE PATHOLOGY, INC 170 (1) 214 - 226 0002-9440 2007/01 [Refereed]
     
    Although demyelination is a cardinal feature in multiple sclerosis, axonal injury also occurs. We tested whether a delay in axonal degeneration could affect the disease severity in two models for multiple sclerosis: experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. We compared wild-type C57BL/6 (B6) mice with C57BL/Wld(s) (Wld) mice, which carry a mutation that delays axonal degeneration. In EAE, both mouse strains were sensitized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide and showed a similar disease onset, MOG-specific lymphoproliferative responses, and inflammation during the acute stage of EAE. However, during the chronic stage, B6 mice continued to show paralysis with a greater extent of axonal damage, demyelination, and MOG-specific lymphoproliferative responses compared with Wld mice, which showed complete recovery. In TMEV infection, only Wld mice were paralyzed and had increased inflammation, virus antigen-positive cells, and TMEV-specific lymphoproliferative responses versus infected B6 mice. Because TMEV can use axons to disseminate in the brain, axonal degeneration in B6 mice might be a beneficial mechanism that limits the virus spread, whereas slow axonal degeneration in Wld mice could favor virus spread. Therefore, axonal degeneration plays contrasting roles (beneficial versus detrimental) depending on the initiator driving the disease.
  • Ikuo Tsunoda; Emily Jane Terry; Benjamin J. Marble; Elias Lazarides; Catherine Woods; Robert S. Fujinami
    BRAIN PATHOLOGY WILEY 17 (1) 45 - 55 1015-6305 2007/01 [Refereed]
     
    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Adhesion molecules play important roles in cell-cell and cell-extracellular matrix (ECM) interactions in inflammation. Blocking the interaction between inflammatory cells and vascular endothelia can prevent cell entry into tissues and harmful inflammatory responses, that is, autoimmunity, but could also limit immunosurveillance by anti-viral T cells in sites of infection or latency. Development of progressive multifocal leukoencephalopathy in patients treated with antibody against very late antigen (VLA)-4 prompted us to explore an alternative therapeutic approach. We used an antibody against the integrin alpha 2, VLA-2, that interacts with ECM, not vascular endothelium. SJL/J mice were sensitized with myelin proteolipid protein (PLP)(139-151) peptide to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Treatment of mice with VLA-2 antibody suppressed clinical signs and CNS inflammation of EAE, when antibody was given immediately after disease onset. In contrast, VLA-4 or VLA-2 antibody treatment of mice during the priming or remission phase of EAE had minor effects on the disease's clinical course. No differences were found in lymphoproliferative responses to PLP139-151 among treatment groups. Data suggest that blocking cell-ECM interactions can be an alternative therapy for MS.
  • NG Carlson; KE Hill; Tsunoda, I; RS Fujinami; JW Rose
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 174 (1-2) 21 - 31 0165-5728 2006/05 [Refereed]
     
    The objective of this study was examine whether the inducible isoform of the enzyme cyclooxygenase (COX-2) was expressed in dying oligodendrocytes in the Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD), an experimental animal model for multiple sclerosis (MS). COX-2 is an enzyme that is tightly coupled to neuronal excitotoxic death. Since neuronal expression of COX-2 contributes to the susceptibility of neurons to excitotoxic death, we asked whether COX-2 was expressed in oligodendrocytes in MS plaques and in lesions during TMEV-IDD. COX-2 was expressed in oligodendrocytes in chronic active lesions from two MS patients. Similar pathology was present in TMEV-IDD spinal cord lesions. COX-2 was expressed in oligodendrocytes four weeks after infection with TMEV coincident with the onset of demyelination. A marker for apoptotic death, activated caspase 3, was present in a subset of oligodendrocytes that expressed COX-2. Oligodendrocyte expression of COX-2 in TMEV-IDD and MS lesions is consistent with a pathological role for this enzyme in demyelination. The presence of the cell death marker (activated caspase 3) with COX-2 in oligodendrocytes is direct evidence linking COX-2 with cell death of oligodendrocytes in these demyelinating diseases. (c) 2006 Elsevier B.V. All rights reserved.
  • JE Libbey; LK Peterson; Tsunoda, I; RS Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 173 (1-2) 135 - 145 0165-5728 2006/04 [Refereed]
     
    A.SW mice sensitized with myelin oligodendrocyte, glycoprotein (MOG)(92-106) is an animal model for progressive multiple sclerosis (MS). We isolated MOG-reactive monoclonal antibodies that were immunoglobulin (Ig)M and polyreactive, similar to natural autoantibodies. Upon analysis of the variable (V) light chains and the diversity (D) and joining (J) regions of V heavy chains, we found they were identical to germ line V(kappa)19/28, J(kappa)5 DFL 16.1(e) and J(H)4, respectively. The sequence of the V-H region had 99.7% and 100% identity at the nucleotide and amino acid levels, respectively, compared with the germ line encoded antibody, P3, of the Q52 family. Although A strain mice have been reported to have an insertion in BAFF-R, the receptor for BAFF (B cell activation factor from the tumor necrosis factor family), which could explain our results, A.SW mice have no mutations in BAFF-R. (c) 2005 Elsevier B.V. All fights reserved.
  • Tsunoda, I; JE Libbey; M Kobayashi-Warren; RS Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 172 (1-2) 85 - 93 0165-5728 2006/03 [Refereed]
     
    From mice infected with the DA strain of Theiler's murine encephalomyelitis virus (TMEV), CD8(+) cytotoxic T lymphocytes (CTLs) could be detected after stimulation with TMEV infected antigen presenting cells (APCs). These CTLs killed not only TMEV infected but also uninfected syngeneic cells. Killing was associated with interferon (IFN)-gamma production in ELISPOT assays. The CTLs were efficiently induced by vaccinia virus encoding DA virus capsid proteins, but not by APCs infected with the GDVII strain of TMEV. The CTLs produced IFN-gamma in response to TMEV infected, but not uninfected, astrocytes. The CTLs could be maintained in the presence of interleukin (IL)-2. We hypothesized that, in DA virus infection, CD8(+) CTLs specific for viral capsid protein could recognize self protein on oligodendrocytes by molecular mimicry, leading to demyelination. (C) 2005 Elsevier B.V All rights reserved.
  • L McCoy; Tsunoda, I; RS Fujinami
    AUTOIMMUNITY TAYLOR & FRANCIS LTD 39 (1) 9 - 19 0891-6934 2006/02 [Refereed]
     
    Polymicrobial infections have been associated with plausible immune mediated diseases, including multiple sclerosis (MS). Virus infection can prime autoimmune T cells specific for central nervous system (CNS) antigens, if virus has molecular mimicry with CNS proteins. On the other hand, infection of irrelevant viruses will induce two types of cytokine responses. Infection with a virus such as lymphocytic choriomeningitis virus (LCMV), can induce interferon (IFN)-alpha/beta production and suppress autoimmunity, while infection with a virus, such as murine cytomegalovirus (MCMV), can activate natural killer (NK), NKT and dendritic cells, resulting in interleukin (IL)-12 and IFN-gamma production. These cytokines can cause bystander activation of autoreactive T cells. We established an animal model, where mice infected with vaccinia virus encoding myelin protein can mount autoimmune responses. However, the mice develop clinical disease only after irrelevant immune activation either with complete Freund's adjuvant or MCMV infection. In this review, we propose that a combination of two mechanisms, molecular mimicry and bystander activation, induced by virus infection, can lead to CNS demyelinating diseases, including MS. Viral proteins having molecular mimicry with self-proteins in the CNS can prime genetically susceptible individuals. Once this priming has occurred, an immunologic challenge could result in disease through bystander activation by cytokines.
  • Tsunoda, I; LQ Kuang; M Kobayashi-Warren; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 79 (23) 14640 - 14646 0022-538X 2005/12 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) causes a demyelinating disease in infected mice which has similarities to multiple sclerosis. Spleen cells from TMEV-infected SJL/J mice stimulated with antigen-presenting cells infected with TMEV resulted in a population of autoreactive CD8(+) cytotoxic T cells that kill uninfected syngeneic cells. We established CD8(+) T cell clones that could kill both TMEV-infected and uninfected syngeneic targets, although infected target cells were killed more efficiently. The CD8(+) T-cell clones produced gamma interferon when incubated with either infected or uninfected syngeneic target cells. Intracerebral injection of the clones into naive mice induced degeneration, not only in the brain, but also in the spinal cord. This suggests that CD8(+) Tcl cells could play a pathogenic role in central nervous system inflammation.
  • Tsunoda, I; JE Libbey; LQ Kuang; EJ Terry; RS Fujinami
    AMERICAN JOURNAL OF PATHOLOGY AMER SOC INVESTIGATIVE PATHOLOGY, INC 167 (6) 1631 - 1646 0002-9440 2005/12 [Refereed]
     
    The mechanism(s) responsible for generating the different forms of multiple sclerosis, primary progressive (PP) and secondary progressive (SP) versus relapsing-remitting (RR), is not well understood. Using myelin oligodendrocyte glycoprotein (MOG)(92-106), we have established animal models that mimic the different types of multiple sclerosis. A.SW mice develop PP or SP-experimental allergic encephalomyelitis (EAE) with large areas of demyelination and high titers of MOG antibody whereas SJL/J mice develop RR-EAE with perivascular T cells and mild demyelination. In A.SW progressive EAE, we found atrophy of the thymus, spleen, and lymph nodes with depletion of T and B cells and massive apoptosis, as demonstrated by immunohistochemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis. To test whether lymphoid apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic thymocytes. Injection of apoptotic cells resulted in greater than 20% of mice developing SP-EAE with ataxia. SJL/J mice with SP-EAE had large areas of demyelination, high MOG antibody titers and atrophic lymphoid organs. Spleen cells from mice with progressive EAE produced less interferon-gamma than those from RR-EAE when stimulated with mitogen. We suggest that induction of lymphoid apoptosis alters the balance of Th1 versus Th2 immune responses and increases MOG antibody production, leading to exacerbation of demyelination and subsequent disease progression.
  • Tsunoda, I; LQ Kuang; IZM Igenge; RS Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 160 (1-2) 122 - 134 0165-5728 2005/03 [Refereed]
     
    We induced experimental allergic encephalomyelitis (EAE) in SJL/J mice, an animal model for multiple sclerosis (MS), using myelin oligodendrocyte glycoprotein (MOG)(92-106) peptide, following ultraviolet (UV) irradiation. While all control mice developed relapsing-remitting (RR)-EAE, UV irradiation induced secondary progressive (SP)-EAE in some of the mice. Although mild demyelination was observed with T cell infiltration in RR-EAE, large demyelinating lesions developed in SP-EAE with massive macrophage and neutrophil infiltration and immunoglobulin deposition, but with little T cell infiltration. UV irradiation induced higher anti-MOG antibody responses. In SP-EAE, lymphoproliferative responses and interferon-gamma production were decreased without alteration of interleukin-4. (c) 2004 Elsevier B.V. All rights reserved.
  • Ikuo Tsunoda; Jane E. Libbey; Mikako Kobayashi-Warren; Robert S. Fujinami
    JOURNAL OF NEUROVIROLOGY SPRINGER 14 17 - 17 1355-0284 2005 [Refereed]
  • Tsunoda, I; TE Lane; J Blackett; RS Fujinami
    MULTIPLE SCLEROSIS ARNOLD, HODDER HEADLINE PLC 10 (1) 26 - 34 1352-4585 2004/02 [Refereed]
     
    Theilers murine encephalomyelitis virus (TMEV) causes demyelination with inflammation of the central nervous system (CNS) in mice and is used as an animal model for multiple sclerosis (MS). Interferon-gamma inducible protein-10 kDa (IP-10) is a CXC chemokine and a chemoattractant for CXCR3(+) T cells. IP-10 mRNA is expressed in the CNS during TMEV infection. However, administration of anti-IP-10 serum caused no difference in clinical signs, inflammation, demyelination, virus persistence or anti-virus antibody response in TMEV infection, while levels of virus specific and autoreactive lymphoproliferation increased. This likely reflects a difference in the pathogenesis of TMEV infection from that of two other animal models for MS, mouse hepatitis virus infection and experimental allergic encephalomyelitis (EAE), where blocking of IP-10 resulted in clinical and histological improvement with suppression of antigen specific lymphoproliferation. In this review, we compare and contrast the roles of IP-10 between the three animal models for MS, and discuss the relevance to MS patients with different clinical courses.
  • Robert S. Fujinami; Diethilde J. Theil; Ikuo Tsunoda; Melina V. Jones; J. Lindsay Whitton
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 10 47 - 48 1355-0284 2004 [Refereed]
  • Ikuo Tsunoda
    Abstracts of the General Meeting of the American Society for Microbiology 2004
  • FUJINAMI, R. S.; TSUNODA, I.
    Abstracts of the General Meeting of the American Society for Microbiology 104 618 - 618 2004
  • Tsunoda, I; LQ Kuang; JE Libbey; RS Fujinami
    AMERICAN JOURNAL OF PATHOLOGY AMER SOC INVESTIGATIVE PATHOLOGY, INC 162 (4) 1259 - 1269 0002-9440 2003/04 [Refereed]
     
    Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler's murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I+ microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in. severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.
  • M Wang; JE Libbey; Tsunoda, I; RS Fujinami
    VIRAL IMMUNOLOGY MARY ANN LIEBERT INC PUBL 16 (1) 45 - 55 0882-8245 2003 [Refereed]
     
    Measles can result in a variety of immunologic defects. Previously we showed that an Epstein-Barr virus-transformed B cell line (B cells), when infected with measles virus, produced a soluble antiproliferative factor that inhibited proliferation of T and B cells. Here we explore the effects of infection by measles virus versus the virus-free soluble antiproliferative factor on B cells. The B cells showed no change in the amounts of interleukin (IL)-2, 10, 12, interferon (IFN)-gamma, or transforming growth factor (TGF)-beta when infected or exposed to the soluble factor. Similarly, B cells showed no change in the expression of class 11 major histocompatibility antigens, LFA-1, ICAM-1, CD19, CD40, CD80, CD86, CD95 (Fas), or CD178 (FasL). Cell cycle analysis showed that measles virus infection caused an accumulation of cells in S and G(2)/M phases with a "sub-G(1)" cell population, while incubation of cells with the soluble factor caused an accumulation in G(0)/G(1). These experiments provide evidence that measles virus causes a profound inhibition of B cell proliferation without distinguishable changes in cytokine profile or cell surface phenotype. Further, it appears that there are two populations of cells affected by infection: one population is growth arrested due to the influence of the immunosuppressive factor and is not infected; a second population that is infected progresses through S phase less efficiently. Alternatively, while both the soluble factor and live virus infection may affect cells in G(0)/G(1) phases, only live virus infection could selectively induce apoptosis of G(0)/G(1) cells, resulting in cell accumulation in S and G(2)/M phases with a build up of "sub-G(1)" cells.
  • Tsunoda, I; LO Kuang; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 76 (24) 12834 - 12844 0022-538X 2002/12 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) belongs to the family Picornaviridae and causes demyelinating disease in the spinal cords of infected mice. Although immune responses have been shown to play an important role in demyelination, the precise effector mechanism(s) is unknown. Potentially autoreactive cytotoxic cells could contribute to the destruction. We tested whether an autoreactive cell induced by TMEV infection mediated cytotoxicity by using a 5-h Cr-51 release assay in SJL/J mice. Spleen cells from TMEV-infected mice were stimulated with irradiated TMEV antigen-presenting cells and used as effector cells. The effector cells differed from conventional cytotoxic T cells since these cells could kill both TMEV-infected and uninfected syngeneic or semisyngenic cell lines (PSJLSV and BxSF11gSV) but could not kill an allogeneic cell line (C57SV). The TMEV-induced autoreactive cells were also different from conventional natural killer (NK) cells or lymphokine-activated killer (LAK) cells, because they could kill neither NK cell-sensitive YAC-1 nor NK cell-resistant P815 and EL4 cells. Induction of autoreactive cells was not detected in vaccinia virus infection. The autoreactive killing required direct cell-to-cell contact and was mediated by a Fas-FasL pathway but not by a perforin pathway. The phenotype of the killer cells was CD3(+) CD4(-) CD8(+). Intracerebral inoculation of the effector cells into naive mice caused meningitis and perivascular cuffing not only in the brain parenchyma but also in the spinal cord, with no evidence of viral antigen-positive cells. This is the first report demonstrating that TMEV can induce autoreactive cytotoxic cells that induce central nervous system pathology.
  • Tsunoda, I; LO Kuang; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 76 (24) 12834 - 12844 0022-538X 2002/12 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) belongs to the family Picornaviridae and causes demyelinating disease in the spinal cords of infected mice. Although immune responses have been shown to play an important role in demyelination, the precise effector mechanism(s) is unknown. Potentially autoreactive cytotoxic cells could contribute to the destruction. We tested whether an autoreactive cell induced by TMEV infection mediated cytotoxicity by using a 5-h Cr-51 release assay in SJL/J mice. Spleen cells from TMEV-infected mice were stimulated with irradiated TMEV antigen-presenting cells and used as effector cells. The effector cells differed from conventional cytotoxic T cells since these cells could kill both TMEV-infected and uninfected syngeneic or semisyngenic cell lines (PSJLSV and BxSF11gSV) but could not kill an allogeneic cell line (C57SV). The TMEV-induced autoreactive cells were also different from conventional natural killer (NK) cells or lymphokine-activated killer (LAK) cells, because they could kill neither NK cell-sensitive YAC-1 nor NK cell-resistant P815 and EL4 cells. Induction of autoreactive cells was not detected in vaccinia virus infection. The autoreactive killing required direct cell-to-cell contact and was mediated by a Fas-FasL pathway but not by a perforin pathway. The phenotype of the killer cells was CD3(+) CD4(-) CD8(+). Intracerebral inoculation of the effector cells into naive mice caused meningitis and perivascular cuffing not only in the brain parenchyma but also in the spinal cord, with no evidence of viral antigen-positive cells. This is the first report demonstrating that TMEV can induce autoreactive cytotoxic cells that induce central nervous system pathology.
  • Tsunoda, I; RS Fujinami
    SPRINGER SEMINARS IN IMMUNOPATHOLOGY SPRINGER-VERLAG 24 (2) 105 - 125 0344-4325 2002/11 [Refereed]
     
    The primary target in multiple sclerosis (MS) is believed to be either myelin itself (myelinopathy) or the myelin-forming cell, the oligodendrocyte (oligodendrogliopathy). Although axonal injury occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from myelin (outside) to the axon (inside) (Outside-In model). Recently, gray matter lesions and axonal injury in normal-appearing white matter have also been reported in MS. This raises two questions. I) Is axonal injury exclusively secondary to myelin damage or from a direct insult to the axon or neurons (axonopathy)? (2) Is the injured axon regarded as only an end result of pathology or disease, or can axonal injury contribute to the spread of secondary damage, including demyelination? The former is raised from the fact that axonal damage has been reported in several virus infections, including human immunodeficiency virus, human T lymphotropic virus 1, herpes simplex virus and coronavirus, which also cause demyelination. The latter possibility where axonal injury leads to other changes is raised from the rather unexpected similarity between spinal cord injury (SCI) and MS where axonal injury, oligodendrocyte apoptosis and demyelination are all present. In SCI, transection of axons leads to delayed oligodendrocyte apoptosis with secondary demyelination. Neurofilament immunostaining of spinal cord sections demonstrates that axonal injury with oligodendrocyte apoptosis also precedes demyelination in an animal model for MS, Theiler's murine encephalomyelitis virus infection. This implies that axonal injury could trigger demyelination. In this instance, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).
  • IJ McCright; Tsunoda, I; JE Libbey; RS Fujinami
    JOURNAL OF NEUROVIROLOGY TAYLOR & FRANCIS INC 8 (2) 100 - 110 1355-0284 2002/04 [Refereed]
     
    The DA strain of Theiler's murine encephalomyelitis viruses (TMEV) causes a central nervous system (CNS) demyelinating disease with viral persistence despite the presence of high serum anti-TMEV antibody titers. The DA virus mutant, T81D, was created to have a mutation at position 81 in loop I of VP1, close to the putative virus receptor binding site. T81D showed slower replication in vitro and in vivo. T81D-infected mice developed anti-TMEV antibody responses with no virus persistence. We tested whether the differences between the viruses were due to alteration in virus-cell interactions, or in the resistance to neutralization by anti-TMEV antibody. Using radiolabeled viruses, we found no difference in binding to permissive cell lines between the mutant and wildtype viruses. In a semipermissive cell line, DA virus bound more efficiently than T81D. During the uncoating step, both viruses decapsidated without the production of stable intermediates and 80% of viruses were eluted or decapsidated after 45 minutes. At the final step of uncoating, however, T81D showed a slower rate of RNA release than DA virus into cells using a photoinactivation assay. Anti-TMEV monoclonal and polyclonal antibodies neutralized T81D virus more efficiently than DA virus in suspension. Further, these anti-TMEV antibodies were able to neutralize viruses that had already attached to cells but not internalized (postadsorption neutralization [PAN]). However, DA virus showed significant resistance to PAN after cells were incubated at 37degreesC compared with T81D-infected cells. The development of resistance to PAN appeared to correlate with the rate of RNA release from virions into cells. In T81D virus infection, the slow RNA release and high susceptibility to neutralization by antibodies would result in a failure to establish virus persistence in vivo. Conversely, rapid RNA release and resistance to neutralization could favor virus persistence in DA virus infection.
  • JE Libbey; Tsunoda, I; RS Fujinami
    VIROLOGY ACADEMIC PRESS INC ELSEVIER SCIENCE 294 (1) 85 - 93 0042-6822 2002/03 [Refereed]
     
    The receptor for Theiler's murine encephalomyelitis virus (TMEV) remains unknown, In vitro, BHK-21 cells are permissive to infection by TMEV. Selecting mutants of BHK-21 cells produced a cell line (BHKR-) resistant to infection by TMEV. Viral persistence was ruled out by immunofluorescent staining for viral antigens. BHKR- cells were nonpermissive to infection even at high multiplicities of infection. In contrast, cells were able to support one round of virus replication when transfected with infectious TMEV RNA. Binding studies indicated that TMEV was unable to attach to these cells. These data are consistent with the BHKR- cells lacking a receptor for TMEV. Interestingly, BHKR- cells were larger in size and had a significant lag In growth after subculture versus BHK-21 cells. This suggests that the TMEV receptor on BHK-21 cells could play an important role in cell growth and morphology under physiologic conditions. BHKR- cells should facilitate the search for TMEV receptors. (C) 2002 Elsevier Science (USA).
  • Ikuo Tsunoda
    Abstracts of the General Meeting of the American Society for Microbiology 2002
  • LIBBEY, J. E.; TSUNODA, I.; FUJINAMI, R. S.
    Abstracts of the General Meeting of the American Society for Microbiology 102 474 - 474 2002
  • Ikuo Tsunoda
    Abstracts of the General Meeting of the American Society for Microbiology 2002
  • TSUNODA, I.; KUANG, L.; LIBBEY, J. E.; et al.
    Abstracts of the General Meeting of the American Society for Microbiology 102 474 - 474 2002
  • Tsunoda, I; YK Wada; JE Libbey; TS Cannon; FG Whitby; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 75 (16) 7494 - 7505 0022-538X 2001/08 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups based on neurovirulence. During the acute phase, DA virus infects cells in the gray matter of the central nervous system (CNS). Throughout the chronic phase, DA virus infects glial cells in the white matter, causing demyelinating disease. Although GDVII virus also infects neurons in the gray matter, infected mice developed a severe polioencephalomyelitis, and no virus is detected in the white matter or other areas in the CNS in rare survivors. Several sequence differences between the two viruses are located in VP2 puff B and VP1 loop II, which are located near each other, close to the proposed receptor binding site. We constructed a DA virus mutant, DApBL2M, which has the VP1 loop II of GDVII virus and a mutation at position 171 in VP2 puff B. While DApBL2M virus replicated less efficiently than DA virus during the acute phase, DApBL2M-induced acute polioencephalitis was comparable to that in DA virus infection. Interestingly, during the chronic phase, DApBL2M caused prolonged gray matter disease in the brain without white matter involvement in the spinal cord. This is opposite what is observed during wild-type DA virus infection. Our study is the first to demonstrate that conformational differences via interaction of VP2 puff B and VP1 loop II between GDVII and DA viruses can play an important role in making the transition of infection from the gray matter in the brain to the spinal cord white matter during TMEV infection.
  • DJ Theil; Tsunoda, I; F Rodriguez; JL Whitton; RS Fujinami
    JOURNAL OF NEUROVIROLOGY NATURE PUBLISHING GROUP 7 (3) 220 - 227 1355-0284 2001/06 [Refereed]
     
    Although many viruses have been isolated from patients with multiple sclerosis (MS), as yet, no one agent has been demonstrated to cause MS. In contrast, epidemiological data indicate that viral infections are associated with exacerbations of MS. Here, we present data showing that virus infections can subclinically prime animals for central nervous system (CNS) autoimmune disease; long after the original infection has been eradicated, a nonspecific challenge/infection can trigger an exacerbation. The priming infectious agent must show molecular mimicry with self-CNS antigens such as glial fibrillary acidic protein (GFAP), myelin associated glycoprotein (MAG) or myelin proteolipid protein (PLP). The subsequent challenge, however, may be nonspecific; complete Freund's adjuvant (CFA), or infection with a recombinant vaccinia virus encoding an irrelevant protein, could trigger CNS disease. In the CNS, we could detect a mononuclear cell infiltration, but no demyelination was found. However, if the pathogenesis of MS is similar to that of this novel animal model for CNS autoimmune disease, our findings could help explain why exacerbations of MS are often associated with a variety of different viral infections.
  • JE Libbey; IJ McCright; Tsunoda, I; Y Wada; RS Fujinami
    JOURNAL OF NEUROVIROLOGY NATURE PUBLISHING GROUP 7 (2) 97 - 104 1355-0284 2001/04 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) belongs the family Picornaviridae. TMEV not only replicates in the gastrointestinal tract but also spreads to the central nervous system (CNS) either by a hematogenous or a neural pathway during natural infection. The DA strain of TMEV infects neurons during the acute phase, and glial cells and macrophages during the chronic phase, leading to a demyelinating disease similar to multiple sclerosis, Different virus-host receptor interactions in the peripheral and the neuronal cells could explain the pathways of viral spread from the peripheral to the CNS and neurons to glial cells. However, the receptor for TMEV remains unknown, PO protein, a 28-31 kD glycoprotein, belongs to the immunoglobulin superfamily and constitutes 50% of the total myelin protein in the peripheral nerve. Other picornaviruses use members of the immunoglobulin superfamily as receptors. Thus we hypothesized PO protein could act as a receptor for TMEV. In a virus overlay assay, radiolabeled TMEV bound to a 28-30 kD protein from the peripheral nerve of wild-type C57BL/6, but no binding was found in the peripheral nerve from PO-knockout mice. TMEV replicated fourfold higher in PO-transfected BW5147.G.1.4 cells than in mock-transfected cells. The increase in virus replication in the PO-transfected cell line was blocked by preincubation of the cells with anti-PO antibody. A virus binding study showed that TMEV bound to PO-transfected cells but not to mock-transfected cells. The use of the PO protein in Schwann cells as a receptor may be one mechanism by which TMEV spreads from the gastrointestinal tract to the CNS.
  • Tsunoda, I; LQ Kuang; DJ Theil; RS Fujinami
    BRAIN PATHOLOGY INT SOC NEUROPATHOLOGY 10 (3) 402 - 418 1015-6305 2000/07 [Refereed]
     
    Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR), Since PP-MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP-MS is immunologically similar to the other forms. The pathogenesis of the PP-MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)(92-106) we have established animal models that mimic different forms of MS in 2 strains of H-2(s) mice, SJL/J and A,SW, We induced experimental allergic encephalomyelitis (EAE) using MOG(92-106) in the presence or absence of supplemental Bordetella pertussis (SP). Although, SJL/J mice developed RR-EAE whether SP was given or not, A,SW mice developed PP-EAE without BP and SPEAE with BP, Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A,SW mice developed large areas of plaquelike demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without SP, high titer serum anti-MOG antibody was detected and the antiMOG IgG2a/lgG1 ratio correlated with survival times of mice, We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR-, PP-, or SP- forms of demyelinating disease in hosts with immunologically different humoral immune responses.
  • DJ Theil; Tsunoda, I; JE Libbey; TJ Derfuss; RS Fujinami
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 104 (1) 22 - 30 0165-5728 2000/04 [Refereed]
     
    DA, GDVII and H101 are neurovirulent strains of Theiler's murine encephalomyelitis virus that cause very different neuropathology and CNS disease when inoculated into SJL/J mice. DA virus causes a chronic demyelinating disease, GDVII virus causes an acute fatal polioencephalomyelitis, and H101 virus causes an acute pachymeningitis with hydrocephalus. Performing RNase protection assays, we detected the same pattern of chemokine (RANTES, MCP-1, IP-10, MIP-1 beta, MIP-1 alpha and MIP-2) mRNA expression in brain and spinal cord during all three infections. In contrast, IFN-beta and IL-6 mRNA were highly expressed only in GDVII virus infection, whereas high levels of LT-alpha mRNA were only found during DA virus infection. Our study demonstrates that proinflammatory cytokines are involved in the neuropathogenesis of CNS disease and modulate the acute and chronic process underlying different pathologic features of disease. (C) 2000 Elsevier Science B.V. All rights reserved.
  • THEIL, D. J.; TSUNODA, I.; RODRIGUEZ, F.; et al.
    Journal of Neurovirology 6 (5) 436 - 436 2000
  • Tsunoda, I; ND Tolley; DJ Theil; JL Whitton; H Kobayashi; RS Fujinami
    BRAIN PATHOLOGY INT SOC NEUROPATHOLOGY 9 (3) 481 - 493 1015-6305 1999/07 [Refereed]
     
    Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing-remitting experimental allergic encephalomyelitis (R-EAE) have been used to investigate the viral and autoimmune etiology of multiple sclerosis (MS), a possible Th1-type mediated disease. DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides, which contain CpG motifs, have been reported to enhance immunostimulation. Our objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert immunostimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vivo. We demonstrated that this bacterially derived DNA could induce interleukin (IL)-12, interferon (IFN)gamma (Th1-promoting cytokines), and IL-6 production as well as activate NK cells. Following pCMV injections, SJL/J mice were infected with TMEV or challenged with encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection exacerbated TMEV-induced demyelinating disease in a dose-dependent manner. Exacerbation of the disease did not correlate with the number of TMEV-antigen positive cells but did with an increase in anti-TMEV antibody. pCMV injection also enhanced R-EAE with increased IFN gamma, and IL-6 responses. These results caution the use of DNA vaccination in MS patients and other possible Th1-mediated diseases.
  • IJ McCright; Tsunoda, I; FG Whitby; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 73 (4) 2814 - 2824 0022-538X 1999/04 [Refereed]
     
    Theiler's murine encephalomyelitis viruses are picornaviruses that can infect the central nervous system. The DA strain produces an acute polioencephalomyelitis followed by a chronic demyelinating disease in its natural bust, the mouse, The ability of DA virus to induce a demyelinating disease renders this virus infection a model for human demyelinating diseases such as multiple sclerosis, Here we describe the generation and characterization of DA virus mutants that contain specific mutations in the viral capsid protein VP1 at sites believed to be important contact regions for the cellular receptor(s). A mutant virus with a threonine-to-aspartate (T81D) substitution in VP1 loop I adjacent to the putative virus receptor binding site exhibited a large-plaque phenotype but had a slower replication cycle in vitro, When this mutant virus was injected into susceptible mice, an altered tropism was seen during the acute stage of the disease and the chronic demyelinating disease was not produced, A virus with a threonine-to-valine substitution (T81V) did not cause any changes in the pattern or extent of disease seen in mice, whereas a virus with a tryptophan substitution at this position (T81W) produced a similar acute disease but was attenuated for the development of the chronic disease. A change in amino acids in a hydrophobic patch located in the wall of the pit, VP1 position 91, to a hydrophilic threonine (V91T) resulted in a profound attenuation of the acute and chronic disease without persistence of virus. This report illustrates the importance of the loop I of VP1 and a site in the wall of the pit in pathogenesis and that amino acid substitutions at these sites result in altered virus-host interactions.
  • ND Tolley; Tsunoda, I; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 73 (2) 993 - 1000 0022-538X 1999/02 [Refereed]
     
    Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler's murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice three times with cDNA encoding VP2 led to partial protection of mice from CNS demyelinating disease as determined by a decrease in clinical symptoms and histopathology. Vaccination of mice with cDNA encoding VP3 also led to a decrease in clinical symptoms. In contrast, mice vaccinated with cDNA encoding VP1 experienced a more severe disease with an earlier onset of clinical signs and enhanced histopathology compared with control mice; There was no correlation between anti-TMEV antibody titers and disease course. These results indicate that DNA immunization can modify chronic virus-induced demyelinating disease and may eventually lead to potential treatments for illnesses such as MS.
  • Tsunoda, I; A Sette; RS Fujinami; C Oseroff; J Ruppert; C Dahlberg; S Southwood; T Arrhenius; LQ Kuang; RT Kubo; RW Chesnut; GY Ishioka
    VACCINE ELSEVIER SCI LTD 17 (7-8) 675 - 685 0264-410X 1999/02 [Refereed]
     
    Using a bipalmitoylated lipopeptide consisting of an ovalbumin helper T-cell epitope covalently linked to an influenza virus cytotoxic T-lymphocyte (CTL) epitope, we addressed possible factors that may be critical for CTL induction. Antigen processing of lipopeptide appears to be required for T-cell induction since there was virtually no in vitro binding of lipopeptide to purified MHC molecules. A major portion of lipopeptide immunogenicity was due to its particulate nature inasmuch as CTL induction in mice correlated with insoluble lipopeptide constructs, whereas more soluble analogs were significantly less immunogenic. Immunohistological analysis of tissue from immunized animals revealed that lipopeptide migration from the s.c. injection site to the spleen could be detected as early as 1 h after immunization and cell-associated lipopeptide was observed on macrophages and dendritic cells, implicating both cell populations in the processing and presentation of lipopeptide particles to CTLs, (C) 1999 Elsevier Science Ltd. All rights reserved.
  • Y Wada; IJ McCright; FG Whitby; Tsunoda, I; RS Fujinami
    JOURNAL OF VIROLOGY AMER SOC MICROBIOLOGY 72 (9) 7557 - 7562 0022-538X 1998/09 [Refereed]
     
    Theiler's murine encephalomyelitis viruses, which are murine picornaviruses, can cause central nervous system inflammatory disease. To study the role of loop II in capsid protein VP1, two mutant viruses of strain DA in which DA loop II amino acids were replaced,vith strain GDVII amino acids were constructed. Infection of mice with the two mutant viruses led to dramatically different patterns of disease.
  • Tsunoda, I; LQ Kuang; ND Tolley; JL Whitton; RS Fujinami
    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY AMER ASSN NEUROPATHOLOGISTS INC 57 (8) 758 - 767 0022-3069 1998/08 [Refereed]
     
    Relapsing-remitting experimental allergic encephalomyelitis (R-EAE) is an animal model for multiple sclerosis (MS). Many potential immunomodulatory strategies for MS have been used first in EAE to assess their effectiveness. Recently, the injection of plasmid DNA has been shown to induce potent humoral and cellular immune responses. The primary aim of our experiments reported here was to determine if vaccination with cDNAs encoding myelin proteolipid protein (PLP) could prime for a PLP-specific immune response and affect subsequent R-EAE. We constructed cDNAs encoding whole PLP (pPLP(all)) or encephalitogenic epitopes PLP139-151 (pPLP(139-151)) and PLP178-191 (pPLP(178-191)). Following DNA injection, we induced R-EAE in SJL/J mice using PLD139-151 or PLP178-191 peptides in adjuvant. All 3 plasmid constructs enhanced R-EAE induced with PLP139-151, and injection of mice with pPLP(all) increased R-EAE induced with PLPall DNA immunization induced higher PLP peptide-specific lymphoproliferative responses than did vector alone following R-EAE induction with IgG1 or IgG2b antibody responses. These data suggest that DNA immunization of PLP can modulate immune responses, leading to enhancement of R-EAE.
  • JW Rose; KE Hill; Y Wada; CIB Kurtz; Tsunoda, I; RS Fujinami; AH Cross
    JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 81 (1-2) 82 - 89 0165-5728 1998/01 [Refereed]
     
    This study evaluated effects of the inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on the neuropathology and clinical disease produced by Theiler's murine encephalomyelitis virus (TMEV) DA strain infection. Treatment with AG was started on day 7, 14, 28 or 66 post-inoculation and continued for a minimum of 21 days, Inflammation, demyelination and axonal necrosis were scored in a blinded fashion on spinal cord sections from each mouse. Reduction in inflammation, demyelination and axonal necrosis was observed in mice treated with AG. Apoptosis within the spinal cord parenchyma and perivascular cuffs was significantly decreased. AG treatment resulted in delayed onset of clinical disease. (C) 1998 Published by Elsevier Science B.V.
  • Tsunoda, I; IJ McCright; LQ Kuang; A Zurbriggen; RS Fujinami
    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY AMER ASSN NEUROPATHOLOGISTS INC 56 (12) 1302 - 1313 0022-3069 1997/12 [Refereed]
     
    The etiology of hydrocephalus is never established in the majority of clinical cases, while various agents, nutritional deficiencies, and genetic factors have been shown to play a role. Viral infection has been recognized as one of the causative factors in the development of hydrocephalus. The wild-type DA strain of Theiler's murine encephalomyelitis virus (TMEV), which belongs to the family Picornaviridae, causes a chronic demyelinating disease in mice with viral persistence that resembles multiple sclerosis. We found that a DA virus variant. hydrocephalus 101 virus (H101 virus), caused hydrocephalus in mice, a condition previously never described for TMEV. To clarify the relationship between DA virus infection and hydrocephalus, we compared H101 virus and wild-type DA virus infection in mice. Using immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), we found that during the acute phase of infection, H101 virus caused macrocephaly and meningitis with the presence of apoptosis, while parenchymal involvement was not evident. Ln contrast, wild-type DA virus caused an acute polioencephalomyelitis with parenchymal infection and apoptosis. During the chronic phase, H101 virus infection caused communicating hydrocephalus without viral persistence, No demyelination and Little or no anti-TMEV antibodies were observed in H101 virus-infected mice. Sequence analysis revealed that H101 virus had mutations in the 5'UTR and capsid protein coding region. Characterization of this new hydrocephalus model gives insight into the possible viral involvement in human hydrocephalus cases of obscure etiology.
  • Tsunoda, I; CIB Kurtz; RS Fujinami
    VIROLOGY ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS 228 (2) 388 - 393 0042-6822 1997/02 [Refereed]
     
    Apoptosis has been observed in neural development and in various neurological diseases, including viral infection and multiple sclerosis. Theiler's murine encephalomyelitis virus is divided into two subgroups based on neurovirulence: the highly neurovirulent GDVII strain produces an acute fatal polioencephalomyelitis in mice, whereas the attenuated DA strain produces demyelination with virus persistence preceded by an acute infection. TUNEL combined with immunocytochemistry was used to detect apoptosis in the central nervous system and to characterize which cell types were involved during the acute stage in both GDVII and DA virus infection and during the chronic stage in DA virus infection. We found that during the acute stage, apoptosis was induced in neurons in both virus infections. However, the number of apoptotic neurons was much greater in GDVII virus-infected mice than in DA virus-infected mice (P < 0.01). During the chronic stage of DA virus infection, apoptotic cells were detected only in the spinal cord white matter. Some of these cells were dual labeled for fragmented DNA and carbonic anhydrase II, an oligodendrocyte marker. Our results indicate that apoptosis of neurons could be responsible for the fatal outcome in GDVII virus infection. In contrast, apoptosis of oligodendrocytes can contribute to the chronic demyelinating DA virus infection. (C) 1997 Academic Press.
  • Tsunoda, I; Y Iwasaki; H Terunuma; K Sako; Y Ohara
    ACTA NEUROPATHOLOGICA SPRINGER VERLAG 91 (6) 595 - 602 0001-6322 1996/06 [Refereed]
     
    Theiler's murine encephalomyelitis viruses (TMEV) are divided into two subgroups on the basis of their different biological activities. The GDVII strain produces acute polioencephalomyelitis in mice, whereas the DA strain produces demyelination with virus persistence in the spinal cord. A comparative study of GDVII and DA strains suggested that low host immune responses are responsible for the development of acute GDVII infection and that the persistence of infected macrophages plays a crucial role in the development of chronic white matter lesions in DA infection. All 78 mice infected with GDVII died or became moribund by day 13, while none of 54 mice infected with DA died. In the acute stage, the distribution of viral antigens in the central nervous system (CNS) tissue was similar in both GDVII and DA infections, although the virus titer was higher in GDVII infection. In DA infection, a substantial number of T cells were recruited to the CNS on day 6 when they were virtually absent in GDVII infection. The titer of neutralizing antibody was already high on day 6 in DA infection but was negligible in GDVII infection. Development of chronic paralytic disease from day 35 of the DA infection was accompanied by focal accumulation of viral antigen-positive macrophages in the spinal white matter. In addition, white matter lesions comparable to those in chronic DA infection were induced in the spinal cord within 7 days after intracerebral injection of DA-infected murine macrophages.
  • Tsunoda, I; RS Fujinami
    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY AMER ASSN NEUROPATHOLOGISTS INC 55 (6) 673 - 686 0022-3069 1996/06 [Refereed]
     
    In this review, we compare and contrast two popular models for multiple sclerosis (MS), Theiler's murine encephalomyelitis virus (TMEV) disease and experimental allergic encephalomyelitis (EAE). These models are used to investigate the viral and autoimmune etiology of MS, respectively. Infection with live TMEV is an essential component of TMEV demyelinating disease. TMEV-specific cellular and humoral immunity and apoptosis of infected cells eliminate virus from the gray matter of the central nervous system (CNS) during the acute phase of TMEV disease. In contrast, during the chronic phase, TMEV persistently infects glial cells and/or macrophages in the white matter. During the chronic phase, recruitment of macrophages, TMEV-specific T cells and antibody, with the induction of apoptosis are harmful to the host, leading to inflammation and demyelination. In EAE, induction of encephalitogenic CD4+ T cells is an important component for disease: After stimulation and activation, these T cells upregulate adhesion molecules and are able to enter the CNS. Thl cytokines augment the recruitment of mononuclear cells in the CNS. Macrophages and/or glial cells secrete cytotoxic factors leading to demyelination in conjunction with B cells secreting anti-myelin antibody. Although immunopathological pathways during the course of the demyelination in TMEV infection and EAE are not always the same, oligodendroglial apoptosis is observed in both models, suggesting that their demyelinating processes share a common terminal pathway and finally lead to quite a similar clinical and pathological picture.
  • Tsunoda I; Endo K; Hirayama K; Saito N; Hida C; Tsukamoto T; Yamamoto T
    Fukushima journal of medical science 1 41 (1) 61 - 69 0016-2590 1995/06 [Refereed]
  • Saito T; Hida C; Tsunoda I; Tsukamoto T; Yamamoto T
    Fukushima journal of medical science 1 40 39 - 44 0016-2590 1994/06 [Refereed]
  • TSUNODA, I; H AWANO; H KAYAMA; T TSUKAMOTO; S UENO; T FUJIWARA; M WATANABE; T YAMAMOTO
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY BRITISH MED JOURNAL PUBL GROUP 57 (5) 635 - 637 0022-3050 1994/05 [Refereed]
     
    A 69-year-old Japanese woman with non-familial amyloidosis had polyneuropathy and profound autonomic neuropathy, and kappa chain monoclonal gammopathy. Immunohistopathological examination showed protein AA and protein AP in the amyloid deposits. She showed involvement of the vestibulocochlear nerve and lattice dystrophy of the cornea. Vestibulocochleopathy and corneal lattice dystrophy have been reported in familial amyloid polyneuropathy type IV, Finnish type, but never in non-familial amyloidosis.
  • TERUNUMA, HIROSHI; OHARA, Y.; MIZOBUCHI, M.; et al.
    Tenth International Conference on AIDS and the International Conference on STD, Vol. 2; The global challenge of AIDS: Together for the future 1994
  • MIZOBUCHI, M.; IWASAKI, Y.; OHARA, Y.; et al.
    Journal of Neuroimmunology 54 (1-2) 183 - 183 1994
  • OHARA, YOSHIRO; IWASAKI, Y.; TERUNUMA, H.; et al.
    Tenth International Conference on AIDS and the International Conference on STD, Vol. 1; The global challenge of AIDS: Together for the future 1994
  • Ikuo Tsunoda; Hidetaka Kanno; Mutsumi Watanabe; Shinya Shimoji; Kazumi Hirayama; Hiroshi Sumita; Teiji Yamamoto
    Auris Nasus Larynx 4 21 (4) 243 - 247 0385-8146 1994 [Refereed]
  • Y IWASAKI; K SAKO; TSUNODA, I; Y OHARA
    ACTA NEUROPATHOLOGICA SPRINGER VERLAG 85 (6) 653 - 657 0001-6322 1993/05 [Refereed]
     
    Using a panel of monoclonal antibodies applicable for identification of cell types in paraffin sections, the prevalence of mononuclear cell infiltrates with different phenotypes was estimated in large areas taken from 11 cases of acute and chronic inflammatory diseases in the human central nervous system. The present study clearly demonstrated a diversity of inflammatory mononuclear cell infiltrates, and the dominance of cell types in individual lesions appeared to be determined by both the nature of the diseases and the age of the lesions. The possible pathognomonic significance of a relatively high prevalence of CD4+CD45RO+ lymphocytes in acute rabies and in a convalescent stage of Japanese encephalitis and subacute sclerosing panencephalitis is discussed.

Books etc

  • <シリーズ>神経内科 Clinical Questions & Pearls「中枢性脱髄疾患」
    角田郁生 (ContributorMSの動物モデルについて教えてください)中外医学社 2018 115-120
  • Neuroinflammation (2nd edition)
    Ikuo Tsunoda (ContributorAnimal models for multiple sclerosis)Elsevier 2017
  • Multiple Sclerosis: A Mechanistic View
    Ikuo Tsunoda (ContributorRole of CD4+ T lymphocytes in pathophysiology of multiple sclerosis.)2016 41-69
  • 実験医学 ラボレポート―留学編―2011年6月号 Vol.29 No.9
    角田郁生 (Contributor望小達大 ルイジアナ州シュリーブポートより-Louisiana State University Health Sciences Center.)羊土社 2011 9784758100724 1460-1462
  • Neuroinflammation, 1st edition
    Ikuo Tsunoda (ContributorAnimal models for multiple sclerosis.)Elsevier 2011 55-79
  • Encyclopedia of Neuroscience
    Ikuo Tsunoda (ContributorCentral nervous system degeneration caused by autoimmune cytotoxic CD8+ T cell clones and hybridomas.)Springer-Verlag GmbH Berlin Heidelberg 2009 619-625
  • Experimental Models of Multiple Sclerosis
    Ikuo Tsunoda (ContributorTMEV and neuroantigens: Myelin genes and proteins, molecular mimicry, epitope spreading and autoantibody-mediated remyelination.)Springer 2005 593-616
  • Persistent Viral Infections.
    Ikuo Tsunoda (ContributorTheiler’s murine encephalomyelitis virus (TMEV).)John Wiley & Sons, Ltd 1999 517-536

Conference Activities & Talks

  • Nguyen CT; Sato F; Nakayama M; Ishigaki H; Itoh Y; Tsunoda I
    Federation of Immunological Societies of Asia-Oceania (FIMSA) Advanced Training Course 2023  Makuhari Messe, Chiba
  • 朴雅美; 尾村誠一; 佐藤文孝; 角田郁生
    第46回日本分子生物学会年会  2023/12  神戸ポートアイランド.兵庫県神戸市
  • 伊井昂河; 畠山悠; 鈴木英彦; 佐藤文孝; 角田郁生; 蛯名博貴; 森田英嗣
    第75回日本細菌学会東北支部総会・学術集会  山形テルサ.山形県山形市.
  • Jaalkhorol M; Dashtseren M; Dashtseren A; Dulamsuren O; Khairat A; Khaidav N; Bat-Orgil B; Baigabul B; Davaadorj G; Tsunoda I
    World congress on osteoporosis, osteoarthritis and musculoskeletal diseases. WCO IOF-ESCEO Congress 2023  CCIB Congress Center, Barcelona  The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) , The International Osteoporosis Foundation (IOF)
     
    Objective: Handgrip strength (HGS) is a simple and reliable measurement of muscle strength. It is an important tool for diagnosing sarcopenia and chronic diseases in the elderly. To investigate HGS in patients with type 2 diabetes mellitus (T2DM) in central and suburban district hospitals in Ulaanbaatar. Methods: The study was conducted using cross-sectional analysis and included 347 participants (209 females, 138 males) over 40 who had T2DM. Patients completed a questionnaire on their lifestyles and clinical information within 20-30 minutes from June 2022 to November 2022. HGS was measured by a handheld dynamometer with maximum effort; two attempts were made with each hand. HGS was defined according to the Asian Working Group for Sarcopenia (AWGS) criteria as low handgrip strength (<26 kg for males and <18 kg for females). Multivariate logistical regression analyses were used to identify low and normal hand grip strength predictors. Results: The study involved 347 patients, with an average age of 60.64±9.56. Of the subjects, 166 (47.8%) had low hand grip strength and 181(52.2%) had normal hand grip strength. Age, BMI, and diabetes duration were significantly associated with HGS in females and males. Also, high and low-level glucose was significantly associated with HGS in females. But regular exercise, alcohol consumption, and smoking status had not significantly associated with HGS. After adjusting for age, odds ratios (OR) for low hand grip strength remained significantly associated with BMI in T2DM men (OR, 1,95; p=0.001; 95%Cl (0,87-1,01) and women (OR, 1,05; p=0.001; 95%Cl (0,95-1,02). Also showed OR for absolute handgrip strength and blood pressure had a significant effect on the hand grip strength in T2DM men (OR, 1,24; p=0.001; 95%Cl (1,14-1,34), women (OR, 1,05; p=0.001; 95%Cl (0,90-1,02). Conclusion: Low hand-grip strength is associated with the BMI of men and women in Mongolian diabetic patients. Therefore, these findings provide epidemiological evidence for the early intervention of reducing muscle strength in patients with type 2 diabetes mellitus.
  • Ikuo Tsunoda
    The 35th International Papillomavirus Conference (IPVC2023)  2023/04
  • 朴雅美; 佐藤文孝; 角田郁生
    第1回 ⽂部科学省 学術研究助成基⾦ 挑戦的研究(開拓) R4年度採択「新規被膜型蛋白質ナノ粒子を用いた細胞性免疫・粘膜免疫誘導型ワクチンの開発」班会議  2023/02  青森県弘前市 アソベの森いわき荘 コンベンションホール 
    【背景・⽬的】 ヘリコバクター・ピロリ菌(HP)はグラム陰性細菌で、胃粘膜に慢性感 染し胃・⼗⼆指腸潰瘍や胃癌の原因となる。さらに、特発性⾎⼩板減少性紫斑病や神経変性疾患などの胃外疾患との関連も報告されている。神経変性疾患ではアルツハイマー型認知症(AD)やパーキンソン病ではHP 感染率が⾼く、多発性硬化症では感染率が低い、との疫学報告が多数ある(Park et al, 2017)。しかしこれらの疾患にHPがどういったメカニズムで作⽤しているのかは不明である。我々はAD に着⽬し、野⽣型及びADモデルマウスにHPを慢性感染させ脳病理を調べた。その結果、いずれの系統も感 染によって脳内でミクログリア活性化を主体とする炎症が起きていることが分かった。本研究はHP 感染が遠隔臓器である脳に炎症を引き起こすメカニズムを明らかにすることを⽬的としている。ほぼ全てのグラム陰性細菌は⾃⾝のタンパク質やDNA/RNA などを内包する外膜⼩胞(outer membrane vesicles: OMV)を形成し菌体外に分泌する。感染細菌が分泌したOMVがホストの⾎流に乗り、毒素を輸送したり、免疫を活性化することが知られている。本発表ではHPのOMVがマウス⽣体内でどういった動態を⽰すのか、またin vitroでは神経細胞、グリア細胞にどういった作⽤を持つのかを報告する。 【⽅法・結果】 HP培養液から濾過・超遠⼼によってOMVを回収した。蛍光標識した OMVを、マウスに投与し体内動態を解析した結果、⽼齢マウスでのみ脳へ移⾏してい ることが分かった。マウス神経細胞Neuro2a とグリア細胞(ミクログリア、アストロ サイト)にOMVを曝露し、細胞増殖能とAD関連タンパク質・炎症関連因⼦を定量し た結果、Neuro2aでは増殖抑制とアミロイドβ蓄積に関連するタンパク質(BACE, PS2)の増加がみられた。ミクログリアとアストロサイトでは増殖促進と炎症性サイトカイン・ケモカインのmRNA増加がみられた。 【結論】 HP 感染によってその感染部位である胃粘膜から離れた脳内で炎症が起こる メカニズムとして、HPが分泌するOMVが⾎⾏性に脳へと運ばれ、グリア細胞を活性 化している可能性が考えられた(Park and Tsunoda, 2022)。 【⽂献】 • Helicobacter pylori and gut microbiota in multiple sclerosis versus Alzheimer's disease: 10 pitfalls of microbiome studies. Ah-Mee Park, Seiichi Omura, Mitsugu Fujita, Fumitaka Sato, Ikuo Tsunoda, Clinical & experimental neuroimmunology 8(3), 2017 • Helicobacter pylori infection in the stomach induces neuroinflammation: the potential roles of bacterial outer membrane vesicles in an animal model of Alzheimer’s disease. Ah-Mee Park, Ikuo Tsunoda, Inflammation and Regeneration 42(1), 2022
  • 角田郁生
    第1回 ⽂部科学省 学術研究助成基⾦ 挑戦的研究(開拓) R4年度採択「新規被膜型蛋白質ナノ粒子を用いた細胞性免疫・粘膜免疫誘導型ワクチンの開発」班会議  青森県弘前市 アソベの森いわき荘 コンベンションホール
  • Khadka S; Omura S; Sato F; Ahmad I; Tsunoda I
    The 51st Annual Meeting of The Japanese Society for Immunology  2022/12  Kumamoto-Jo Hall, Kumamoto
  • Roles of anti-glycolipid antibodies in different animal models of multiple sclerosis with distinct clinical courses
    Sato F; Nakamura Y; Moriguchi K; Park A-M; Kuwahara M; Omura S; Khadka S; Ahmad I; Kusunoki S; Tsunoda I
    The 51st Annual Meeting of The Japanese Society for Immunology  Kumamoto-Jo Hall, Kumamoto
  • Jaalkhorol M; Dulamsuren O; Dashtseren A; Byambajav E-A; Khaidav N; Bat-Orgil B; Jigmeddorj B; Chuluunbaatar A; Tsunoda I
    The 14th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)  2022  Singapore 
    PACTRIMS Programme & Abstracts p25-26
  • マウス胃のピロリ菌慢性感染は脳に神経炎症と遺伝子発現変化を誘導する
    朴雅美; 尾村誠一; 佐藤文孝; 角田郁生
    第41回日本認知症学会学術集会/第37回日本老年精神医学会  2022/11  東京国際フォーラム. 東京都千代田区
  • Platelets play a detrimental role in an animal model of viral myocarditis
    Ahmad I; Sato F; Omura S; Khadka S; Park A-M; Gavins FNE; Tsunoda I
    The 69th Annual Meeting of the Japanese Society for Virology  Dejima Messe Nagasaki, Nagasaki
  • Scientific evaluation of alleged experimental findings for side effects of HPV vaccines  [Invited]
    松村謙臣; 角田郁生
    第60回日本癌治療学会学術集会  神戸コンベンションセンター.神戸市
  • 角田 郁生; 朴 雅美; 尾村 誠一; 堀田芙美香; 城玲央奈; スンダル・カドカ; イジャーズ・エフマド; 森口 幸太; 佐藤 文孝
    第34回日本神経免疫学会学術集会  出島メッセ長崎、長崎県長崎市
  • 森口 幸太; 中村 優美和; 朴 雅美; 佐藤 文孝; 桑原 基; スンダル・カドカ; 尾村 誠一; イジャーズ・エフマド; 楠 進; 角田 郁生
    第34回日本神経免疫学会学術集会  出島メッセ長崎、長崎県長崎市
  • Curcumin monoglucuronide (CMG) suppresses an autoimmune model of multiple sclerosis with altered gut microbiota
    Khadka S; Omura S; Sato S; Nishio K; Kakeya H; Tsunoda I
    10th Graduate School Summit for Kindai University  2022/10  近畿大学 東大阪キャンパス
  • Platelet depletion ameliorates virus-induced myocarditis
    Ahmad I; Sato F; Omura S; Khadka S; Park A-M; Gavins FNE; Tsunoda I
    10th Graduate School Summit for Kindai University  2022/10  Kindai University, Higashiosaka, Osaka
  • 角田郁生
    日本学術振興会 R021食と未病マーカー産学協力委員会第10回定例研究会 (2022年度 第2回)  2022/08  Zoomウェビナー  日本学術振興会 R021食と未病マーカー産学協力委員会
  • Platelet depletion ameliorates a viral model of multiple sclerosis  [Invited]
    Ahmad I; Omura S; Sato F; Khadka S; Park A-M; Sakiyama N; Gavins FNE; Tsunoda I
    Kindai University Faculty of Medicine  2022/07  近畿大学医学部大講堂.大阪府大阪狭山市
  • 西尾和人; 角田郁生; 岡田斉; 坂井和子; 上嶋一臣; 櫻井俊治
    新学術領域研究 「化学コミュニケーションのフロンティア」 取りまとめシンポジウム  2022/07  京都大学大学院薬学研究科・藤多記念ホール
  • Omura S; Khadka S; Sato F; Nakamura Y; Nishio N; Kakeya H; Tsunoda I
    “Symposium 79, Chemical Communications through Natural and Synthetic Bioactive Compounds.” 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2021). The 2nd International Symposium on Chemical Communication (ISCC2021)
  • Khadka S; Omura S; Sato F; Nishio N; Kakeya H; Tsunoda I
    The 50th Annual Meeting of the Japanese Society for Immunology  2021/12  Nara Kasugano International Forum IRAKA, Nara
  • Sato F; Omura S; Park A-M; Khadka S; Nishio N; Nakamura Y; Katsuki A; Nishio K; Gavins FNE; Tsunoda I
    The 50th Annual Meeting of the Japanese Society for Immunology  Nara Kasugano International Forum IRAKA, Nara
  • Anti-glycolipid antibodies are associated with clinical courses of four autoimmune and viral models for multiple sclerosis  [Not invited]
    Nakamura Y; Park A-M; Sato F; Kuwahara M; Khadka S; Omura S; Ahmad I; Kusunoki S; Tsunoda I
    The 44th Annual Meeting of the Molecular Biology Society of Japan
  • Distinct bacteria in the gut associate with IgA levels in the central nervous system in picornavirus-induced acute and chronic myelitis models
    Sato F; Omura S; Park A-M; Khadka S; Nakamura Y; Katsuki A; Nishio K; Gavins FNE; Tsunoda I
    The 68th Annual Meeting of the Japanese Society for Virology  2021/11  神戸  日本ウイルス学会
  • スンダル・カドカ; 尾村誠一; 佐藤文孝; 中村優美和; 甲木蒼紫; 崎山奈美江; 朴雅美; 西尾和人; 掛谷秀昭; 角田郁生
    第80回近畿大学医学会学術講演会  2021/07  近畿大学医学部大講堂.大阪府大阪狭山市
  • 胃粘膜ピロリ菌感染マウス脳内免疫細胞活性化:アルツハイマー型認知症との関連  [Not invited]
    朴雅美; 岩室優; 角田郁生
    第42回日本炎症・再生医学会  2021/07
  • 角田郁生
    日本神経免疫学会WEB講演会「神経免疫疾患と多発性硬化症」  2021/05
  • 角田郁生; 尾村誠一; 佐藤文孝; 崎山奈美江; Sundar Khadka; 中村優美和; 朴雅美; 藤田貢
    第32回日本神経免疫学会学術集会  2020/10
  • 角田郁生; 鳥山重光
    第27回日本免疫毒性学会学術年会  2020/09
  • ウイルス感染・ワクチンによる免疫性神経疾患~神経免疫学・神経ウイルス学の立場からHPVワクチンの推奨  [Invited]
    角田郁生
    第39回日本思春期学会総会・学術集会  2020/08
  • 朴雅美; 尾村誠一; 佐藤文孝; 藤田貢; 角田郁生
    第24回腸内細菌学会学術集会  2020/06
  • ヒト―細菌叢間 化学コミュニケーションの理解と炎症性腸疾患・がん・がん免疫  [Invited]
    西尾和人; 坂井和子; 上嶋一臣; 櫻井俊治; 角田郁生; 岡田斉
    「化学コミュニケーションのフロンティア」の第7回公開シンポジウム  2020/06
  • 多発性硬化症動物モデルにおける水溶性プロドラッグ型クルクミン CMG の治療効果と腸内細菌叢変化  [Invited]
    角田郁生; 尾村誠一; 佐藤文孝; Sundar Khadka; 中村優美和; 甲木蒼紫; 西尾和人; 掛谷秀昭; 角田郁生
    2019/12
  • ピロリ菌が神経細胞・中枢神経に及ぼす影響  [Not invited]
    朴雅美; 佐藤文孝; 甲木蒼紫; 中村優美和; 角田郁生
    第42回日本分子生物学会年会  2019/12
  • Immune system and Theiler’s virus-induced animal model for seizures/epilepsy  [Invited]
    Tsunoda I; Sato F; Omura S; Khadka S; Fujita M; Park A-M; Katsuki A; Nakamura Y; Sakiyama N; Lindeberg F
    The 53rd Annual Congress of the Japan Epilepsy Society  2019/11
  • Alteration of microbiota and immune gene expressions in the central nervous system in a picornavirus-induced acute flaccid myelitis model  [Invited]
    Sato F; Omura S; Park A-M; Fujita M; Khadka S; Nishio K; Tsunoda I
    The 67th Annual Meeting of the Japanese Society for Virology  2019/10
  • First National Hepatitis B Viral Load Testing in Nepal: Laboratory Perspective for Nepalese National Treatment Guideline  [Invited]
    Khadka S; Tsunoda I; Omura S; Sato F; Park A-M; Fujita M; Sakiyama N; Nakamura Y; Katsuki A; Pandit R; Dhital S; Baniya JB; Tiwari S; Shrestha B; Pandit S; Sharma M; Mishra SK
    The 67th Annual Meeting of the Japanese Society for Virology  2019/10
  • ウイルス性脳脊髄炎モデルにおける中枢神経病態と腸内細菌叢との関連性  [Invited]
    尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; スンダル・カドカ; 角田郁生
    第24回日本神経感染症学会総会学術大会  2019/10
  • 微生物感染・ワクチンと免疫性神経疾患―ヒトパピローマウイルスワクチン推奨再開にむけて  [Invited]
    角田郁生
    第13回南大阪産婦人科臨床懇話会  2019/10
  • 多発性硬化症ウイルスモデルにおける腸内細菌叢の変化と中枢神経系炎症性脱髄病変との関連  [Invited]
    尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; カドカ スンダル; 角田郁生
    第31回日本神経免疫学会学術集会  2019/09
  • Altered microbiota could affect distinct CNS immune gene expressions in the Theiler's virus model of MS  [Invited]
    Sato F; Omura S; Park A-M; Fujita M; Khadka S; Sakiyama N; Katsuki A; Nakamura Y; Nishio K; Tsunoda I
    Sendai Conference 2019  2019/06
  • 炎症に起因する病態における宿主とその微小環境との相互作用は生体リガンドを介した化学コミュニケーションとして作用する  [Invited]
    坂井和子; 櫻井俊治; 上嶋一臣; 角田郁生; 尾村誠一; 高濱隆幸; 西尾和人
    「化学コミュニケーションのフロンティア」の第5回公開シンポジウム  2019/06
  • 多発性硬化症における中枢神経系と腸内細菌叢のコミュニケーション  [Invited]
    角田郁生; 尾村誠一; 西尾和人
    第19回日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会 共催シンポジウム 化学コミュニケーションのフロンティア  2019/06
  • Efficacy of antiretroviral therapy in HIV positive patients in Nepal  [Invited]
    Khadka S; Omura S; Sato F; Park A-M; Fujita M; Sakiyama N; Nakamura Y; Katsuki A; Tsunoda I
    The 78th Kindai University Medical Association Meeting  2019/06
  • 多発性硬化症ウイルスモデルにおける中枢神経系炎症性病態と腸内細菌叢変化との関連性の検討  [Not invited]
    尾村誠一; 佐藤文孝; 朴 雅美; 藤田 貢; 角田郁生
    第23回腸内細菌学会  2019/06
  • Glatiramer acetate is safe for a virus-induced demyelinating disease model  [Invited]
    Sato F; Omura1 S; Martinez NE; Range T; Ekshyyan L; Minagar A; Alexander JS; Tsunoda I
    60th Annual Meeting of the Japanese Society of Neurology  2019/05
  • 近畿大学における国費外国人留学生 (大学院生) の受け入れ  [Invited]
    角田郁生; スンダル・カドカ
    近畿大学大学院医学研究科 平成30年度第1回FD研究集会, 大学院医学研究科共通実験的・臨床的研究D項目“医学研究科の更なる国際化を目指して”  2019/02
  • Communication between CNS and gut microbiota in a viral model for multiple sclerosis  [Invited]
    Omura S; Nishio K; Tsunoda I
    The 1st International Symposium on Chemical Communication (ISCC2019)  2019/01
  • TLR4 exacerbates a novel model of myocarditis induced with a picornavirus.  [Not invited]
    Sato F; Omura S; Kawai E; Martinez N.E; Acharya MM; Reddy PC; Alexander JS; Tsunoda I
    The 47th Annual Meeting of the Japanese Society for Immunology  2018/12
  • New diagnostic algorithm of HIV/AIDS in Nepal  [Not invited]
    Khadka S; Tsunoda I
    4th Dianken Microbiology Colloquium  2018/10
  • Theiler’s virus-induced myocarditis model with acute viral replication, subacute T cell infiltration and chronic fibrosis in the heart  [Not invited]
    Sato F; Omura S; Martinez NE; Cliburn EA; Acharya MM; Reddy PC; Alexander JS; Tsunoda I
    The 66th Annual Meeting of the Japanese Society for Virology  2018/10
  • A Severe Infectious Mononucleosis-Like Disease in IL-27-Deficient Mice Infected with Murine γ-Herpesvirus 68  [Not invited]
    Kanai K; Park A-M; Tsunoda I; Yoshie O
    he 66th Annual Meeting of the Japanese Society for Virology  2018/10
  • Bioinformatics analyses identified phase-specific heart biomarkers and blood surrogate markers for a mouse model of viral myocarditis.  [Not invited]
    Omura S; Sato F; Park A-M; Fujita M; Alexander JS; Kilgore PCSR; Cvek U; Tsunoda I
    Research and Industry Day (RAID) 2018 Conference  2018/10
  • 転写因子T-bet過剰発現は神経向性ウイルス感染において致死的となる  [Not invited]
    佐藤文孝; 川合英一郎; Nicholas E. Martinez; 尾村誠一; 藤田貢; 朴雅美; 高橋智; 楊景堯; 角田郁生
    第23回日本神経感染症学会総会・学術大会  2018/10
  • Exploratory factor analysis determines latent factors associated with distinct sets of anti-glycolipid antibodies in Guillain-Barré syndrome  [Not invited]
    Omura S; Shimizu K; Kuwahara M; Morikawa M; Fujita M; Park A-M; Sato F; Pedio E; Kusunoki S; Tsunoda I
    The 30th Annual Meeting of the Japanese Society for Neuroimmunology  2018/09
  • Distinct sets of anti-glycolipid antibodies are associated with latent factors in Guillain-Barré syndrome by exploratory factor analysis.  [Invited]
    Omura S; Shimizu K; Kuwahara M; Morikawa M; Fujita M; Park A-M; Sato F; Kusunoki S; Tsunoda I
    14th International Congress of Neuroimmunology (ISNI 2018)  2018/08
  • Potential prebiotic β-glucan curdlan differently alters viral versus autoimmune models of MS.  [Invited]
    Sato F; Martinez NE; Omura S; Park A-M; Fujita M; Minagar A; Alexander JS; Tsunoda I
    The 8th Sendai Conference 2018  2018/07
  • Neurotropic virus infection downregulates lymphatic molecules, suppressing lymphocyte exit from the central nervous system.  [Not invited]
    Tsunoda I; Omura S; Sato F; Park A-M; Fujita M; Sakiyama N; Minagar A; Phillip CSR Kilgore PCSR; Cvek U; Alexander JS
    The 12th China-Japan International Conference of Virology  2018/05
  • Bioinformatics analyses identified phase-specific heart biomarkers and blood surrogate markers for a mouse model of viral myocarditis.  [Not invited]
    Omura S; Sato F; Park A-M; Fujita M; Alexander JS; Kilgore PCSR; Cvek U; Tsunoda I
    Louisiana Biomedical Research Network (LBRN) 16th Annual Meeting  2018/01
  • 免疫病理学、バイオインフォマティクスによる多発性硬化症動物モデルの研究  [Invited]
    角田郁生
    第47回神戸ラボ全体研究会議  2017/11
  • 多発性硬化症ウイルスモデルリンパ管分子マーカーの主成分分析(PCA)による解析  [Invited]
    角田郁生
    多発性硬化症セミナー 宮崎大学医学部 宮崎市 宮崎県  2017/10
  • Bioinformatics analyses identified phase-specific heart biomarkers and blood surrogate markers for a mouse model of viral myocarditis  [Not invited]
    Omura S; Sato F; Park A-M; Fujita M; Alexander JS; Kilgore CSR; Cvek U; Tsunoda I
    The 65th Annual Meeting of the Japanese Society for Virology  2017/10
  • 次世代シークエンシングを用いたウイルス性脳脊髄炎モデルの解析; リンパ管分子発現低下が免疫細胞の中枢神経内停滞に関連する  [Not invited]
    尾村誠一; 佐藤文孝; 藤田貢; 朴雅美; J. Steven Alexander、Phillip; C.S.R. Kilgore; rška Cvek; 角田郁生
    第22回日本神経感染症学会総会・学術大会  2017/10
  • 転写因子T-bet過剰発現は神経向性ウイルス感染を増悪させる  [Not invited]
    佐藤文孝; 川合英一郎; ニコラス・マルチネス; 尾村誠一; 藤田貢; 朴雅美; 崎山奈美江; 高橋智; 楊景堯; 角田郁生
    第29回日本神経免疫学会  2017/10
  • Factor Analysis Associated Anti-Glycolipid Antibodies with Clinical Data in Guillain-Barré Syndrome  [Not invited]
    Omura S; Shimizu K; Morikawa M; Kuwahara M; Kawamura T; Mori T; Kusunoki S; Tsunoda I
    Informatics in Biology, Medicine and Pharmacology (IIBMP2017)  2017/09
  • Bioinformatics analysis determined the CNS and peripheral lymphoid surrogate biomarker candidates between two distinct EAE models for progressive multiple sclerosis  [Not invited]
    Omura S; Sato F; Martinez NE; Park A-M; Cvek U; Minagar A; Alexander JS; Tsunoda I
    XXIII World Congress of Neurology  2017/09
  • Viral infection activates myelin-specific T cells, triggering MS-like CNS inflammatory demyelination  [Not invited]
    Sato F; Omura S; Park A-M; Fujita M; Stokes KY; Tsunoda I
    XXIII World Congress of Neurology  2017/09
  • ウイルスによる自然発症自己免疫モデルの増悪  [Not invited]
    佐藤文孝; 尾村誠一; 朴雅美; 藤田貢; 角田郁生
    第76回近畿大学医学会学術講演会  2017/07
  • Rを用いた主成分分析による多発性硬化症マウスモデル病態・病理像関連バイオマーカーの同定  [Not invited]
    尾村誠一; 佐藤文孝; Nicholas E. Martinez; 朴雅美; 藤田貢; Phillip; C.S.R. Kilgore; rška Cvek; Marjan Trutschl、Alireza Minagar; J; Steven Alexander; 角田郁生
    第76回近畿大学医学会学術講演会  2017/07
  • 肺線維化における細胞周期制御因子の役割  [Not invited]
    朴雅美; 義江修; 角田郁生
    第38回日本炎症・再生医学会  2017/07
  • An RNA virus triggers inflammatory demyelination in the central nervous system by activating anti-myelin autoimmune T cells  [Invited]
    Sato F; Legaux KN; Creason TG; Omura S; Park A-M; Fujita M; Stokes KY; Tsunoda I
    7th Sendai Conference 2017  2017/07
  • Computational analysis determined the homogeneities and heterogeneieties between two distinct EAE models for progressive multiple sclerosis.  [Invited]
    Omura S; Sato F; Martinez NE; Park A-M; Fujita M; Kilgore PCSR; Cvek, U; Trutschl M; Minagar A; Alexander JS; and; Tsunoda I
    7th Sendai Conference 2017  2017/07
  • マウスγヘルペスウイルスを用いた Epstein-Barr virus 肝炎の発症機序の研究  [Not invited]
    金井亨輔; 朴雅美; 渡部明子; 有川智博; 安居輝人; 吉田裕樹; 角田郁生; 義江修
    第32回中国四国ウイルス研究会  2017/06
  • タイラーウイルス誘導性脳脊髄炎モデルにおける制御性T細胞の役割  [Not invited]
    佐藤文孝; Nicolas Martinez; Fridrik Karlsson; 尾村誠一; 朴雅美; 藤田貢; Matthew Grishma; 角田郁生
    第27回日本サイトメトリー学会学術集会  2017/06
  • 多発性硬化症の遺伝子プロファイル主成分分析PCAによるリンパ管バイオマーカーの同定  [Invited]
    角田郁生; 尾村誠一; 佐藤文孝; 朴雅美; 藤田貢
    第90回日本産業衛生学会 アレルギー・免疫毒性研究会  2017/05
  • A novel function of p130 protein in pulmonary fibrosis  [Not invited]
    Ikuo Tsunoda
    ConBio2017 生命科学系学会合同年次大会 = 第40回日本分子生物学会年会 + 第90回日本生化学会大会  2017
  • HSP27ノックダウンによる線維芽細胞の細胞周期停止におけるE2F-4の役割  [Not invited]
    朴 雅美; 角田郁生
    第39回日本分子生物学会  2016/11
  • ウイルス感染によって誘発される炎症性脱髄と軸索変性のメカニズム  [Not invited]
    角田郁生; 佐藤文孝; 尾村誠一; 崎山奈美江; 朴雅美; 藤田貢
    第21回日本神経感染症学会総会・学術大会  2016/10
  • 進行型多発性硬化症モデルでは血管接着分子の発現増加、BBB/リンパ管分子の発現減少が病因に相関する  [Not invited]
    尾村誠一; 佐藤文孝; J. Steven Alexander, Phillip; C.S.R. Kilgore; Urska Cvek; Marjan Trutschl; 角田郁生
    第28回日本神経免役学会学術集会  2016/09
  • 多発性硬化症と心筋炎のウイルスモデル  [Invited]
    角田郁生
    近畿大学医学会総会  2016/06
  • L-35は気道における好酸球浸潤を抑制する  [Not invited]
    金井 亨輔; 朴 雅美; 角田 郁生; 吉田 裕樹; 義江 修
    第81回日本インターフェロン・サイトカイン学会  2016/05
  • Multiple sclerosis as a vascular disease.  [Invited]
    Minagar A; Tsunoda I; Alexander JS
    The 6th Annual International Society for Neurovascular Disease (ISNVD) Scientific Meeting  2016/04
  • Upregulation of lymphatic markers and vascular adhesion molecules in CNS RNAseq transcriptome of a viral model for multiple sclerosis.  [Invited]
    Omura S; Sato F; Alexander JS; Kilgore PCSR; Cvek U; Trutschl M; Tsunoda I
    The 6th Annual International Society for Neurovascular Disease (ISNVD) Scientific Meeting  2016/04
  • Monocytes/macrophages play a contributing role in lymphangiogenesis independent of their role in intestinal inflammation.  [Not invited]
    Becker F; Vowinkel T; Rijcken E; Tsunoda I; Ostanin DV; Alexander JS
    133. Kongress Deutsche Gesellschaft für Chirurgie  2016/04
  • Brain endothelial cells segregate lymphatic-venous biomarkers into microparticles following inflammatory cytokine stimulation.  [Not invited]
    Yun JW; Minagar A; Tsunoda I; Alexander JS
    Experimental Biology 2016, April 2-6, 2016, San Diego, California  2016/04
  • Contributions of monocytes to gut inflammation in acute and chronic colitis models.  [Invited]
    Becker F; Gavins FN; Vowinkel T; Tsunoda I; Rijcken E; Ostanin DV; Alexander JS
    11th Congress of European Crohn’s and Colitis Organization (ECCO)  2016/03
  • Models of MS and Disease Progression  [Invited]
    Ikuo Tsunoda
    Multiple Sclerosis Summit. University of Utah  2015/12
  • Th1/Th2 imbalance by “gain-of-function” mutations cause fatal Theiler’s virus infection in mice.  [Not invited]
    Sato F; Kawai E; Martinez NE; Omura S; Stewart EC; Takahashi S; Yoh K; Tsunoda I
    2015 Southeast Regional IDeA Meeting  2015/11
  • Th1 transcription factor T-bet, but not the Th2 transcription factor GATA3, overexpression is detrimental in neurotropic viral infection in the CNS.  [Not invited]
    Sato F; Kawai E; Martinez NE; Omura S; Cliburn EA; Takahashi S; Yoh K; Tsunoda I
    34th Annual Meeting of the American Society for Virology (ASV)  2015/07
  • The role of Th17 and regulatory T cells in viral and autoimmune models for multiple sclerosis  [Invited]
    Ikuo Tsunoda
    Kinki University Medical Association  2015/05
  • IL-1 receptor antagonist (Anakinra) restores mesenteric lymphatic muscle cell tonic contractility suppressed by acute or chronic colitis conditioned media in vitro.  [Not invited]
    Al-Kofahi M; Becker F; Wagn Y; Tsunoda I; Woolard M; Jordan PA; Boktor M; Alexander JS
    Digestive Disease Week (DDW) 2015  2015/05
  • Reduced intestinal leukocyte exit heightens the severity of DSS colitis in a murine model of lymphovascular deficiency.  [Not invited]
    Becker F; Witte M; Boktor M; Tsunoda I; Jordan PA; Bernas M; Abreo F; Orr AW; Alexander JS
    Digestive Disease Week (DDW) 2015  2015/05
  • A viral model for multiple sclerosis; Theiler’s virus infection.  [Invited]
    Ikuo Tsunoda
    University at Buffalo, the State University of New York, Neurology Grand Rounds  2015/05
  • Endothelial dysfunction in neurodegenerative disease.  [Not invited]
    Yun JW; Stevenson E; Omura S; Sato F; Tsunoda I; Minagar A; Becker F; Castor T; Xiao A; Alexander JS
    5th Annual Meeting of the International Society for Neurovascular Disease (ISNDV)  2015/03
  • Fluid dynamic influences on Cerebrovascular endothelial activation responses.  [Not invited]
    Stevenson EV; Yun JW; Omura S; Sato F; Tsunoda I; Minagar A; Becker F; Castor T; Couraud P-O; Romero IA; Weksler B; Alexander JS
    5th Annual Meeting of the International Society for Neurovascular Disease (ISNDV)  2015/03
  • Specificity of antibody binding in anti-Yo antibody mediated Purkinje cell cytotoxicity.  [Not invited]
    Greenlee JE; Clardy SL; Clawson SA; Wood B; Hill KE; Tsunoda I; Carlson NG
    139th Annual Meeting, American Neurological Association (ANA), October 12-14, Baltimore, Maryland  2014/10
  • Phase-specific cardiac biomarkers and blood surrogate markers for a mouse model of myocarditis induced by cardiovirus.  [Not invited]
    Omura S; Sato F; Kawai E; Martinez NE; Cvek U; Trutschl M; Alexander JS; Tsunoda I
    33rd Annual Meeting of the American Society for Virology (ASV)  2014/06
  • Inside-Out model of multiple sclerosis: Theiler’s virus infection.  [Invited]
    Tsunoda I; Martinez NE; Omura S; Kawai E; Sato F
    International Workshop and Oral Presentation: MS Model 2, the 55th Annual Meeting of the Japanese Society of Neurology.  2014/05
  • Autoimmune and viral models of MS in Th2-biased GATA3 transgenic mice.  [Invited]
    Sato F; Fernando V; Omura S; Martinez NE; Kawai E; Shafiei F; Acharya MM; Takahashi S; Yoh; Tsunoda I
    International Workshop and Oral Presentation: MS Model 1, the 55th Annual Meeting of the Japanese Society of Neurology  2014/05
  • Th17 biased transgenic mice show exacerbation of an autoimmune model for MS.  [Invited]
    Martinez NE; Sato F; Omura S; Kawai E; Takahashi S; Yoh; Tsunoda I
    International Workshop and Oral Presentation: MS Model 1, the 55th Annual Meeting of the Japanese Society of Neurology  2014/05
  • Brain biomarkers and spleen surrogate markers for primary progressive MS models.  [Invited]
    Omura S; Cvek U; Trutschl M; Sato F; Martinez NE; Kawai E; Fernando V; Morris LA; Acharya M; Shafiei F; Alexander JS; Tsunoda I
    International Workshop and Oral Presentation: MS Model 1, the 55th Annual Meeting of the Japanese Society of Neurology.  2014/05
  • IL-1β inhibits contraction of intestinal lymphatic smooth muscle - Implications for chronic gut inflammation.  [Not invited]
    Al-Kofahi M; Alexander JS; Woolard M; Tsunoda I; Wang Y; Boktor M; Jordan PA; Sheth A; Zawieja DC; Muthuchamy M; von der Weid P-Y; Ostanin D; Pinto K; Becker F
    Digestive Disease Weak (DDW) 2014  2014/05
  • Computational multivariate analyses for phase-specific biomarker identification in novel in vivo and in vitro viral myocarditis models induced by cardiovirus.  [Not invited]
    Shafiei F; Omura S; Kawai E; Sato F; Martinez NE; Fernando V; Morris L; Alexander JS; Cvek U; Trutschl M; Tsunoda I
    63rd Annual Scientific Session & Expo of the American College of Cardiology (ACC.14)  2014/03
  • Theiler’s virus infection: Animal models for multiple sclerosis and myocarditis.  [Invited]
    Ikuo Tsunoda
    Texas Tech University Health Sciences Center  2013/11
  • Natural Killer T Cells Play Protective Roles in Cardiovirus-Induced Myocarditis by Induction of Anti-Viral and Regulatory Cytokines.  [Not invited]
    Sato F; Omura S; Martinez NE; Kawai E; Pearson SF; Fernando V; Acharya MM; C.V. Ganta CV; Alexander JS; Ajuebour MN; Taniguchi M; Tsunoda I
    American Heart Association (AHA), Basic Cardiovascular Sciences (BCVS) 2013 Scientific Sessions  2013/07
  • Determination of Phase-specific Biomarkers of Viral Myocarditis Induced by Theiler’s virus Using Multivariate Analyses of Viral Genome, Troponin, Transcriptome and Echocardiography Data.  [Not invited]
    Kawai E; Omura S; Sato F; Martinez NE; Fernando V; Rollyson P; Cvek U; Trutschl M; Tsunoda I
    American Heart Association (AHA), Basic Cardiovascular Sciences (BCVS) 2013 Scientific Sessions  2013/07
  • Computational analysis of microarray gene expression patterns discriminates the acute viral versus subacute immune phases of myocarditis induced by cardiovirus.  [Not invited]
    Omura S; Sato F; Kawai E; Martinez NE; Pearson SF; Rollyson P; Cvek U; Trutschl M; Tsunoda I
    32nd Annual Meeting of the American Society for Virology (ASV)  2013/07
  • Comparative uptake and cytotoxicity of anti-Hu and anti-Ri antibodies in rat cerebellar slice cultures.  [Not invited]
    Greenlee JE; Clawson S; Wood B; Hill K; Tsunoda I; Carlson NG
    American Academy of Neurology 65th Annual Meeting, March 16-23, 2013, San Diego, California  2013/03
  • Th17 bias renders mice susceptible to a viral model for multiple sclerosis.  [Not invited]
    Martinez NE; Sato F; Omura S; Kawai E; Takahashi S; Yoh K; Tsunoda I
    11th International Society for Neuroimmunology (ISNI) Congress  2012/11
  • Chemokine and autophagy-related genes in novel in vivo and in vitro models for viral myocarditis.  [Not invited]
    Kawai E; Omura S; Sato, F; Martinez NE; Chaitanya GV; Claycomb WC; Alexander JS; Tsunoda I
    American Heart Association (AHA), Basic Cardiovascular Sciences (BCVS) 2012 Scientific Sessions  2012/07
  • Detrimental role of Toll-like receptor 4 in cardiovirus-induced myocarditis.  [Not invited]
    Sato F; Omura S; Martinez NE; Kawai E; Chaitanya GV; Alexander JS; Tsunoda I
    American Heart Association (AHA), Basic Cardiovascular Sciences (BCVS) 2012 Scientific Sessions  2012/07
  • Upregulation of chemokines and interferon-associated genes in a novel model for myocarditis induced by cardiovirus infection.  [Not invited]
    Omura S; Sato F; Martinez NE; Chaitanya GV; Claycomb WC; Alexander JS; Tsunoda I
    31st Annual Meeting of the American Society for Virology (ASV)  2012/07
  • Combining visualization with data mining for bioinformatics-driven discovery.  [Not invited]
    Rollyson P; Tsunoda I; Omura S; Trutschl M; Cvek U
    NIH, NIGMS Fourth Biennial National IDeA Symposium of Biomedical Research Excellence (NISBRE)  2012/06
  • Th17 bias renders mice susceptible to virus-induced demyelinating disease.  [Not invited]
    Martinez NE; Sato F; Omura S; Kawai E; Takahashi S; Yoh; Tsunoda I
    NIH, NIGMS Fourth Biennial National IDeA Symposium of Biomedical Research Excellence (NISBRE)  2012/06
  • Bioinformatics analysis of microarray data in cardiomyocytes and neuronal cells infected with Theiler’s virus  [Not invited]
    Omura S; Sato F; Martinez NE; Kawai E; Trutschl M; Cvek U; Tsunoda I
    NIH, NIGHS Fourth Biennial National IDeA Symposium of Biomedical Research Excellence (NISBRE)  2012/06
  • Curdlan, a Th17 cell inducer, plays contrasting roles in viral model for multiple sclerosis.  [Not invited]
    Sato F; Martinez E; Omura S; Alexander S; Minagar A; Tsunoda I
    Annual Meeting of the American Academy of Neurology  2012/04
  • Role of Toll-like receptor (TLR)4 in a viral model for myocarditis.  [Not invited]
    Sato F; Omura S; Martinez NE; Chaitanya GV; Alexander JS; Tsunoda I
    American Society for Microbiology (ASM) South Central Branch Annual Meeting  2011/12
  • Theiler’s virus infection: Animal models for multiple sclerosis and myocarditis.  [Not invited]
    Tsunoda I; Omura S; Sato F; Martinez NE; Karlsson F; Grisham MB; Chaitanya GV; Alexander JS
    American Society for Microbiology (ASM) South Central Branch Annual Meeting  2011/12
  • Regulatory T cells play contrasting roles in a viral model for multiple sclerosis.  [Not invited]
    Martinez, NE; Karlsson, F; Sato F; Omura S; Minagar A; Grisham MB; Tsunoda I
    The American Neurological Association (ANA) 136th Annual Meeting  2011/09
  • Curdlan, a Th17 cell inducer, plays contrasting roles in Theiler's virus infection.  [Not invited]
    Sato F; Martinez NE; Omura S; Alexander JS; Tsunoda I
    Southeast Regional IDeA Meeting  2011/09
  • Regulatory T cells play a detrimental role in a viral model for multiple sclerosis.  [Not invited]
    Martinez, NE; Karlsson F; Sato F; Omura S; Grisham MB; Tsunoda I
    Southeast Regional IDeA Meeting,  2011/09
  • Resveratrol, a red wine component, exacerbates autoimmune and viral models for multiple sclerosis.  [Invited]
    Ikuo Tsunoda
    Asahikawa Medical College  2011/09
  • Axonal degeneration in autoimmune and viral models for multiple sclerosis: Inside-Out model.  [Invited]
    Ikuo Tsunoda
    Hokkaido University Health Sciences Seminar  2011/09
  • Resveratrol, a red wine component, exacerbates autoimmune and viral models for multiple sclerosis.  [Invited]
    Ikuo Tsunoda
    The 330th Tsukuba Molecular Life Science Seminar  2011/09
  • Curdlan, a Th17 cell inducer, was both detrimental and protective in Theiler's virus infection.  [Not invited]
    Sato F; Martinez NE; Omura S; Alexander JS; Tsunoda I
    The International Union of Microbiological Societies (IUMS). XV International Congress of Virology  2011/09
  • Is MS a homogenous or heterogenous disease? Insight from Th1 and Th17 cytokines in autoimmune and viral models for RR-MS versus PP-MS.  [Not invited]
    Omura S; Sato F; Martinez, NE; Tsunoda I
    The Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting  2011/06
  • Resveratrol, a red wine polyphenol component, exacerbated autoimmune and viral models for MS with increased CNS inflammation.  [Not invited]
    Sato F; Martinez NE; Omura S; Carlson NG; Rose JW; Tsunoda I
    The Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting  2011/06
  • Ephrin/Eph receptor expression on brain microvascular endothelial cells and microparticles: regulation by inflammatory cytokines.  [Not invited]
    Alexander JS; Ganta CV; Orr AW; Funk S; Yurdagul A; Cromer W; Mathis JM; Erdreich-Epstein A; Nagra RM; Minagar A; Tsunoda I; Sato F; Martinez N; Omura S
    BrainPET2011. XXVth International Symposium on Cerebral Blood Flow, Metabolism and Function and the Xth International Conference on Quantification of Brain Function with PET.  2011/05
  • Possible neuroprotection and Th17 modulation by a red wine component, resveratrol, in a mouse model for multiple sclerosis, Theiler’s virus infection.  [Not invited]
    Sato F; Carlson NG; Rose JW; Wood BL; Minagar A; Tsunoda I
    62nd American Academy of Neurology, April 10-17, Toronto, Canada  2011/04
  • Roles of Th1 and Th17 cells in autoimmune and viral models for relapsing-remitting versus progressive multiple sclerosis.  [Not invited]
    Omura S; Sato F; Martinez, NE; Kennett NJ; Tsunoda I
    63rd Annual Meeting of the American Academy of Neurology  2011/04
  • Resveratrol, a red wine polyphenol component, exacerbated CNS inflammation in animal models for MS.  [Not invited]
    Sato F; Martinez NE; Omura S; Carlson NG; Rose JW; Tsunoda I
    Neuroscience Research Day. The Shreveport Chapter of the Society for Neuroscience and the Department of Pharmacology, Toxicology, and Neuroscience. Louisiana State University Health Sciences Center  2011/03
  • Resveratrol, a red wine component, exacerbated viral and autoimmune models for multiple sclerosis.  [Not invited]
    Sato F; Martinez NE; Omura S; Carlson NG; Rose JW; Tsunoda I
    Louisiana Biomedical Research Network (LBRN) 9th Annual Meeting  2011/01
  • Anti-Yo and anti-Hu antibodies affect different neuronal populations and induce cell death by different mechanisms in rat cerebellar slide cultures.  [Not invited]
    Ikuo Tsunoda
    Greenlee JE, Clawson SA, Hill KE, Wood BL, Tsunoda I and Carlson NG.  2010/10
  • Resveratrol, a red wine component, exacerbated MOG-induced EAE.  [Not invited]
    Sato F; Martinez NE; Carlson NG; Rose JW; Tsunoda I
    The 10th International Congress of Neuroimmunology, October 26-30, Barcelona, Spain  2010/10
  • Axonal degeneration in autoimmune and viral models for multiple sclerosis: Inside-Out model.  [Invited]
    Ikuo Tsunoda
    The University of Basel. "Genetic Approaches in Medical Research" Lecture Series.  2010/10
  • Neuroprotection and suppression of IL-17A and IFN-gamma production by resveratrol, a red wine component, in neurotropic CNS Theiler's virus Infection.  [Not invited]
    Sato F; Carlson NG; Rose JW; Wood BL; Martinez NE; Tsunoda I
    010 Louisiana NCRR/IDeA Biomedical Research Symposium, Baton Rouge, Louisiana  2010/01
  • Possible neuroprotection by a red wine component, resveratrol, in an animal model for multiple sclerosis.  [Not invited]
    Sato F; Carlson NG; Rose JW; Wood BL; Tsunoda I
    Neuroscience Research Day. The Shreveport Chapter of the Society for Neuroscience and the Department of Pharmacology, Toxicology, and Neuroscience. Louisiana State University Health Sciences Center, Shreveport, Louisiana  2009/09
  • Axonal degeneration in viral and autoimmune models for multiple sclerosis: Inside-Out model.  [Invited]
    Ikuo Tsunoda
    Tohoku Medical Society  2009/06
  • Axonal degeneration in animal models for multiple sclerosis: Inside-Out model.  [Invited]
    Ikuo Tsunoda
    Research Institute of Environmental Medicine, Nagoya University  2009/06
  • Inflammation, demyelination, neurodegeneration, and neuroprotection in the pathogenesis of a viral model for multiple sclerosis.  [Not invited]
    Tsunoda I; Carlson NG; Kirkman NJ; Doty DJ; Saijoh S; Rose JW
    A joint symposium supported by High-Tech Research Center Grant and Japan Health Sciences Foundation International Research Grant on Animal Models for Human Diseases. Izumisano, Osaka, Japan  2009/06
  • Possible neuroprotection by a red wine component, resveratrol, in CNS neurotropic virus infection.  [Not invited]
    Tsunoda I; Carlson NG; Wood BL; Hasanovic F; Rose JW
    Tsunoda I, Carlson NG, Wood BL, Hasanovic F and Rose JW  2009/06
  • Viral infection leads to CD8+ T cells with dual specificities to virus and self.  [Not invited]
    Fujinami RS; Tsunoda I
    The 9th International Symposium on NeuroVirology. Miami Beach, Florida  2009/06
  • Axonal degeneration as a self-destructive defense mechanism against neurotropic virus.  [Invited]
    Ikuo Tsunoda
    Louisiana State University Health Sciences Center.  2009/02
  • Axonal degeneration in viral and autoimmune models for multiple sclerosis: Inside-Out model  [Invited]
    Ikuo Tsunoda
    The 483rd Brain Institute Conference, Kyushu University School of Medicine  2009/02
  • Autoimmune cytotoxic CD8+ T cells in Theiler’s virus infection.  [Invited]
    Ikuo Tsunoda
    Kinki University School of Medicine  2009/01
  • Compartmental neurodegeneration as a protection mechanism against neurotropic virus infection  [Invited]
    Ikuo Tsunoda
    Hiroshima University School of Medicine  2009/01
  • Axonal degeneration in neurotropic virus infection.  [Invited]
    Ikuo Tsunoda
    Tohoku University Graduate School of Medicine  2009/01
  • Axonal degeneration in viral and autoimmune models for multiple sclerosis: Inside-Out model  [Invited]
    Ikuo Tsunoda
    The University of Cincinnati, Neurology Grand Rounds  2009/01
  • Viral infection of the CNS leads to CD8+ T cells with dual specificities to virus and self  [Not invited]
    Fujinami RS; Tsunoda I
    Keystone Symposium Multiple Sclerosis.  2009/01
  • Possible neural protection by a red wine component, resveratrol, in a viral model for multiple sclerosis.  [Not invited]
    Tsunoda I; Carlson NG; Wood BL; Hasanovic F; Rose JW
    Keystone Symposium Multiple Sclerosis  2009/01
  • Treatment of a viral model for MS with a red wine component, resveratrol.  [Not invited]
    Tsunoda I; Carlson NG; Rojas M; Hasanovic F; Rose JW
    World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS), ACTRIMS + ECTRIMS + LACTRIMS. Montreal, Canada  2008/09
  • Can axonal degeneration be beneficial or detrimental in neurotropic virus infection and autoimmune encephalitis?  [Invited]
    Ikuo Tsunoda
    Institut Pasteur of Shanghai, Chinese Academy of Sciences  2008/06
  • Axonal degeneration as a self-destructive defense mechanism against neurotropic virus infection  [Not invited]
    Tsunoda I; Tanaka T; Hasanovic F; Fujinami RS
    American Society for Investigative Pathology (ASIP) Annual Meeting at Experimental Biology 2008, San Diego, California  2008/04
  • Roles of CD1d-restricted Va14+ NKT cells in Theiler’s virus infection, a viral model for multiple sclerosis.  [Not invited]
    Tsunoda I; Tanaka T; Taniguchi M; Hasanovic F; Fujinami RS
    The 95th American Association of Immunologist (AAI) Annual Meeting at Experimental Biology 2008, San Diego, California  2008/04
  • Contrasting roles of axonal degeneration in viral and autoimmune models for multiple sclerosis.  [Invited]
    Ikuo Tsunoda
    The 13th Neuroscience Seminar, The Juzen Medical Society Kanazawa University  2007/11
  • Can axonal degeneration be beneficial or detrimental in an autoimmune versus viral model of multiple sclerosis?  [Invited]
    Ikuo Tsunoda
    Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd  2007/10
  • Contrasting roles of axonal degeneration in virus infection and autoimmune disease. Animal models for multiple sclerosis and post-polio syndrome.  [Invited]
    Ikuo Tsunoda
    21. Hokkaido University  2007/10
  • Does axonal degeneration precede demyelination in MS? An Inside-Out model.  [Invited]
    Ikuo Tsunoda
    The Brain Institute, The University of Utah, Multiple Sclerosis Research in Utah  2007/10
  • Axonal degeneration in viral and autoimmune models for multiple sclerosis  [Invited]
    Ikuo Tsunoda
    Kinki University Medical Association  2007/10
  • Detection of West Nile virus antigen in the brain using immunohistochemistry.  [Not invited]
    Hasanovic F; Tsunoda I; Morrey JD; Siddharthan V; Fujinami RS
    UCUR 2007, February 2, Salt Lake City, Utah  2007/02
  • Viral infection and neurological diseases.  [Not invited]
    Fujinami RS; McCoy LL; Tsunoda I; Whitton JL
    The 8th International Congress of Neuroimmunology, October 16-19, Nagoya, Japan  2006/10
  • Axonal transport of toxic lectin from the PNS targets inflammatory demyelinating lesions to sites of Wallerian degeneration in the CNS in Theiler’s virus infection: Lesion development from the axon (inside) to the myelin (outside).  [Not invited]
    Tsunoda I; Tanaka T; Saijoh Y; Doyle SE; Terry EJ; Fujinami RS
    The 8th International Congress of Neuroimmunology, October 16-19, Nagoya, Japan  2006/10
  • Autoimmune Cytotoxic CD8+ T cells in Theiler’s Murine Encephalomyelitis Virus Infection.  [Invited]
    Ikuo Tsunoda
    Iwate Medical College  2006/10
  • Contrasting roles of axonal degeneration in autoimmune versus viral models for MS.  [Not invited]
    Ikuo Tsunoda
    The 2006 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting. Scottsdale, Arizona  2006/05
  • Axonal injury in multiple sclerosis: Inside-Out model  [Invited]
    Ikuo Tsunoda
    Kinki University School of Medicine  2005/11
  • Multiple Sclerosis and Axon Injury  [Invited]
    Ikuo Tsunoda
    Molecular Medical Science Institute, Otsuka Pharmaceutical Co. Ltd.  2005/11
  • Autoreactive cytotoxic CD8+ T cells in Theiler’s murine encephalomyelitis virus infection  [Invited]
    Ikuo Tsunoda
    Fukushima Medical University School of Medicine  2005/11
  • A novel infections animal model for seizure disorders.  [Not invited]
    Smith MCP; Tanaka T; Kirkman NJ; McCoy LL; Tsunoda I; Fujinami RS
    American Neurological Association 130th Annual Meeting. September 25-28, San Diego, California  2005/09
  • TMEV infection leading to demyelination: Role for CD8+ autoreactive T cells  [Not invited]
    Tsunoda I; Libbey JE; Kobayashi-Warren M; Fujinami RS
    Third International Conference on Polyomaviruses and Human Diseases: Basic and Clinical Perspectives. Providence, Rhode Island, USA  2005/09
  • The Inside out model of multiple sclerosis  [Invited]
    Ikuo Tsunoda
    Multiple Sclerosis Update Salt Lake City  2005/05
  • Dying oligodendrocytes express COX-2 in Theiler’s virus infection, an animal model for MS  [Not invited]
    Carlson NG; Hill KE; Tsunoda I; Fujinami RS; Rose JW
    American Academy of Neurology, Miami Beach, FL  2005/04
  • Polyreactivity, lymphocytotoxicity and CNS disease modulation by two MOG92-106 monoclonal antibodies.  [Not invited]
    Peterson LK; Tsunoda I; Tanaka T; Masaki T; Fujinami RS
    Central Nervous System Inflammation: Mechanisms, Consequences and Therapeutic Strategies. Keystone Symposium, Snowbird, Utah  2005/01
  • Interferon-γ ELISPOT assay for delineation of epitope specificity of autoreactive cytotoxic T cell clones and hybridomas established from Theiler’s virus infection.  [Not invited]
    Kobayashi-Warren M; Tsunoda I; Kuang L-Q; Libbey JE; Fujinami RS
    Central Nervous System Inflammation: Mechanisms, Consequences and Therapeutic Strategies. Keystone Symposium, Snowbird, Utah  2005/01
  • Is the lack of axonal injury in C57BL/Wlds mice beneficial or detrimental in animal models for multiple sclerosis?  [Not invited]
    Tsunoda I; Tanaka T; Terry EJ; Fujinami RS
    Central Nervous System Inflammation: Mechanisms, Consequences and Therapeutic Strategies. Keystone Symposium, Snowbird, Utah  2005/01
  • Retrograde axonal transport of toxic lectin targets inflammatory demyelinating lesions to the site of Wallerian degeneration  [Invited]
    Ikuo Tsunoda
    Tohoku University School of Medicine  2004/11
  • Axonal injury in animal models of multiple sclerosis.  [Invited]
    Ikuo Tsunoda
    Fukushima Medical University School of Medicine  2004/11
  • Inside-Out versus Outside-In models for virus induced demyelination: Axonal damage triggering demyelination  [Invited]
    Ikuo Tsunoda
    Iwate Medical College. Neuroscience seminar  2004/11
  • Viruses can silently prime and trigger CNS autoimmune disease.  [Not invited]
    Fujinami RS; Theil DJ; Tsunoda I; Jones MV; Whitton JL
    6th International Symposium on NeuroVirology. Sardina, Italy  2004/09
  • Generation and characterization of natural autoantibodies in an animal model for multiple sclerosis.  [Not invited]
    Peterson LK; Tsunoda I; Masaki T; Fujinami RS
    FASEB Summer Research Conferences. Neuro-Immune Interactions: Physiological and Pathological Relevance. Tucson, Arizona  2004/08
  • Viruses Can Silently Prime or Protect and/or Trigger CNS Autoimmune Disease.  [Not invited]
    Fujinami RS; Theil DJ; Tsunoda I; Jones MV; Whitton JL
    12th International Congress of Immunology and 4th Annual Conference of FOCIS, Montreal, Canada  2004/07
  • VP1 of TMEV is required for the generation of autoreactive T cells.  [Not invited]
    Fujinami RS; Tsunoda I
    American Society for Microbiology, 104th General Meeting, New Orleans, Louisiana  2004/05
  • Ultraviolet irradiation alters autoimmune responses leading to disease progression in an animal model for multiple sclerosis  [Not invited]
    Terry EJ; Tsunoda I; Fujinami RS
    18th National Conference on Undergraduate Research (NCUR), Indianapolis, Indiana  2004/04
  • Lesion development from the axon (inside) to the myelin (outside) in Theiler’s virus infection, Inside-Out model: Retrograde axonal transport of toxic lectin targets inflammatory demyelinating lesions to the site of Wallerian degeneration.  [Not invited]
    Tsunoda I; Libbey JE; Igenge IZM; Fujinami RS
    Fifth International Symposium of NeuroVirology--HIV Molecular and Clinical Neuroscience Workshop, Baltimore, Maryland  2003/09
  • Induction of autoreactive CD8+ cytotoxic T cells during Theiler’s murine encephalomyelitis virus infection: Implications for Autoimmunity.  [Not invited]
    Tsunoda I; Fujinami RS
    Fourth International Symposium on Neurovirology/Tenth Conference on Neuroscience of HIV Infection (Conjoint Meeting), Düsseldorf, Germany  2002/06
  • Use of a BHK-21 cell mutant resistant to infection with Theiler’s murine encephalomyelitis virus to search for the receptor.  [Not invited]
    Libbey JE; Tsunoda I; Fujinami RS
    American Society for Microbiology, 102nd General Meeting, Salt Lake City, Utah  2002/05
  • Axonal injury heralds demyelination in Theiler’s murine encephalomyelitis virus infection, animal model for multiple sclerosis  [Not invited]
    Tsunoda I; Kuang L-Q; Libbey JE; Fujinami RS
    American Society for Microbiology, 102nd General Meeting, Salt Lake City, Utah  2002/05
  • Virus infections that protect against or silently prime and trigger autoimmune disease.  [Not invited]
    Theil DJ; Tsunoda I; Rodriguez F; Whitton JL; Fujinami RS
    Keystone Symposium on Molecular and Cellular Biology: Molecular Aspects of Viral Immunity, Keystone, Colorado  2001/04
  • Viruses can silently prime for autoimmune CNS disease.  [Not invited]
    Theil DJ; Tsunoda I; Rodriguez F; Whitton JL; Fujinami RS
    Third International Symposium on NeuroVirology 2000, San Francisco, California  2000/09
  • Viruses can silently prime and trigger autoimmune disease.  [Not invited]
    Theil DJ; Tsunoda I; Rodriguez F; Whitton JL; Fujinami RS
    2000 FASEB Summer Research Conferences, Neural Immune Interactions in Injury and Disease: Pathways to Therapy. Copper Mountain, Colorado  2000/06
  • Splenic autoreactive cytotoxic response in Theiler’s murine encephalomyelitis virus (TMEV) infection.  [Not invited]
    Tsunoda I; Cannon TS; Fujinami RS
    American Society for Virology, 18th Annual Meeting, University of Massachusetts, Amherst, Massachusetts  1999/07
  • Exacerbation of viral and autoimmune models for multiple sclerosis by bacterial DNA.  [Invited]
    Ikuo Tsunoda
    Fukushima Medical University School of Medicine  1999/04
  • Chronic progressive EAE induced with MOG peptide, possible role of NK1.1+ T cell and Th2-type immune response.  [Not invited]
    Tsunoda I; Kuang L-Q; Theil DJ; Fujinami RS
    Keystone Symposia on Molecular and Cellular Biology, Effects of Inflammation in the CNS, Taos, New Mexico  1999/03
  • Chemokine and cytokine mRNA expression in GDVII, DA and H101 strains of TMEV infection.  [Not invited]
    Theil DJ; Tsunoda I; Libbey JE; Fujinami RS
    Keystone Symposia on Molecular and Cellular Biology, Infections of the Nervous System: Host-Pathogen Interactions, Taos, New Mexico  1999/03
  • Substitution of loop II of VP-1 of DA strain with loop II of the GDVII strain of Theiler’s murine encephalomyelitis virus alters neurovirulence, viral persistence and demyelination.  [Not invited]
    Wada Y; McCright IJ; Whitby FG; Tsunoda I; Fujinami RS
    EUROPIC ’98, Xth Meeting of the European Study Group on the Molecular Biology of Picornaviruses, Jena, Germany  1998/09
  • Enhancement of Theiler’s murine encephalomyelitis virus (TMEV) infection by immunization with plasmid DNA.  [Not invited]
    Ikuo Tsunoda
    Tsunoda I, Tolley, ND, Whitten JL, Kuang L-Q and Fujinami RS.  1998/05
  • Apoptosis in Theiler’s murine encephalomyelitis virus (TMEV) infection and experimental allergic encephalomyelitis (EAE).  [Not invited]
    Tsunoda I; Kurtz CIB; Fujinami RS
    Society for Experimental Neuropathology, Miami, Florida  1996/10
  • Apoptosis as a possible mechanism for the central nervous system leading to demyelinating disease.  [Not invited]
    Tsunoda I; Kurtz CIB; Fujinami RS
    Cell Biology of Virus Entry, Replication and Pathogenesis, Keystone Symposia on Molecular and Cellular Biology, Santa Fe, New Mexico  1996/02
  • Suppression of acute active EAE with a derivative of mycophenolic acid.  [Not invited]
    Mizobuchi M; Iwasaki Y; Ohara Y; Terunuma H; Sako K; Tsunoda I; Kaneko Y; Mimura T; Okumura K
    IVth International Congress of Neuroimmunology, Amsterdam, Netherland  1994/10
  • A comparative study on acute and chronic diseases induced by two subgroups of Theiler's murine encephalomyelitis viruses (TMEV).  [Not invited]
    Tsunoda I; Ohara Y; Sako K; Terunuma H; Mizobuchi M; Iwasaki Y
    XIIth International Congress of Neuropathology, Toronto, Canada  1994/09
  • Transcriptional activation of TNF- in HIV infected monocyte/macrophage lineage cell lines.  [Not invited]
    Terunuma H; Ohara Y; Mizobuchi M; Tsunoda I; Iwasaki Y
    XIIth International Congress of Neuropathology, Toronto, Canada  1994/09
  • Suppression of acute active experimental allergic selective reduction of CD4+CD45RC cells in the peripheral blood in Lewis rats.  [Not invited]
    Mizobuchi M; Sako K; Iwasaki Y; Ohara Y; Terunuma H; Tsunoda I
    XIIth International Congress of Neuropathology, Toronto, Canada  1994/09
  • Establishment of human monocytic cells (THP-1) infected with human T-cell leukemia virus type I (HTLV-I).  [Not invited]
    Ohara Y; Iwasaki Y; Tsunoda I; Terunuma H; Mizobuchi M
    XIIth International Congress of Neuropathology, Toronto, Canada  1994/09
  • Transcriptional alteration of TNF- and IL-6 in an HIV-infected monocyte/macrophage lineage cell lines.  [Not invited]
    Ikuo Tsunoda
    Tenth International Conference on AIDS, Yokohama, Japan  1994/08
  • Latent infection of human T-cell Leukemia type I (HTLV-I) in human monocytic cell (THP-1).  [Not invited]
    Ohara Y; Iwasaki Y; Terunuma H; Tsunoda I; Mizobuchi M
    Tenth International Conference on AIDS, Yokohama, Japan  1994/08
  • Anti-very late antigen-4 antibody suppresses acute active experimental allergic encephalomyelitis in Lewis rats.  [Not invited]
    Sako K; Iwasaki Y; Ohara Y; Tsunoda I; Okumura K
    69th Annual Meeting American Association of Neuropathologists  1993/06
  • ベンジン吸入常習によるn-hexane polyneuropathyの1例  [Not invited]
    遠藤雅俊; 角田郁生; 平山和美; 角田裕; 塚本哲朗; 山本悌司
    第50回日本神経学会東北地方会  1992 
    臨床神経学32(6), 661, 1992
  • Crow-Fukase症候群の1例.  [Not invited]
    角田郁生; 平山和美; 飛田兆一; 渡辺多佳子; 山本悌司
    第50回日本神経学会東北地方会  1992 
    臨床神経学32(6), 657, 1992
  • 末梢神経生検の扇形細裂標本(福山法)による検討  [Not invited]
    斎藤佐; 渡辺多佳子; 菅野真澄; 鈴木等; 斎藤直史; 角田郁生; 杉山泰二; 飛田兆一; 粟野裕行; 平山和美; 角田裕; 香山久江; 塚本哲朗; 山本悌司
    第32回日本神経学会総会  1991/05
  • 両側蝸牛前庭障害を合併したneuro-Behcet病の1例  [Not invited]
    角田郁生; 下地眞哉; 斎藤直史; 粟野裕行; 平山和美; 山本悌司; 菅野秀貴; 大谷巌
    第49回日本神経学会東北地方会  1991 
    臨床神経学32(1), 99, 1992
  • A型アミロイド・ニューロパチーの一例  [Not invited]
    角田郁生; 平山和美; 斎藤佐; 角田裕; 塚本哲朗; 山本悌司; 鈴木修一
    第48回日本神経学会東北地方会  1991 
    臨床神経学31(6), 686, 1991
  • 著名な自律神経障害を呈したAA型アミロイドニューロパシー.  [Not invited]
    角田郁生; 香山久江; 杉山泰二; 菅野真澄; 飛田兆一; 粟野裕行; 平山和美; 斎藤佐; 角田裕; 塚本哲朗; 山本悌司
    第2回福島県老年神経疾患研究発表会  1990
  • 胃切除後に出現した亜急性連合性脊髄変性症.  [Not invited]
    角田郁生; 粟野裕行; 斎藤佐; 渡辺多佳子; 塚本哲朗; 山本悌司
    第47回日本神経学会東北地方会  1990 
    臨床神経学31(2)、227, 1991.

MISC

Awards & Honors

  • 2008 American Association of Immunologists (AAI) Junior Faculty Travel Grant Award
     
    受賞者: Ikuo Tsunoda
  • 2006 The Consortium of Multiple Sclerosis Centers (CMSC) Travel Award
     
    受賞者: Ikuo Tsunoda
  • 1996 The Educational Commission for Foreign Medical Graduates ECFMG Certification
     certification number 0-449-653-5 
    受賞者: Ikuo Tsunoda

Research Grants & Projects

  • 日本学術振興会:科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 城 玲央奈; 角田 郁生; 松村 謙臣
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Pioneering)
    Date (from‐to) : 2022/06 -2025/03 
    Author : 森田 英嗣; 角田 郁生; 田中 伸幸; 蝦名 博貴
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 角田 郁生
     
    中枢神経系(CNS)の炎症性疾患である多発性硬化症(multiple sclerosis, MS) の発症頻度には地域差があることから、その発症には免疫素因のみならず、特にウイルス感染が関わることも示唆されている。MS は、免疫素因のある個体がウイルスに暴露された時に発症に至ると推察されるが、ウイルス感染がいかに CNS炎症の引き金になるかは解明されていない。本研究では、ミエリン特異的 T 細胞受容体を過剰発現させたトランスジェニックマウスである2D2 マウスを「免疫素因を有する個体」のモデルとして使用し、ウイルス感染がCNS炎症の引き金となる機序を明らかにすることを目的とする。CNS炎症を誘導するウイルスおよびウイルス由来 PAMPs の同定を目的とし、2D2 マウス腹腔内に 複数のウイルスあるいはウイルスゲノム(一本鎖RNA、二本鎖 RNA)を投与したところ、RNA ウイルスであるタイラーウイルス(Theiler's murine encephalomyelitis virus, TMEV)投与群でCNS に炎症細胞浸潤と免疫関連遺伝子の発現、なかでもIgAの発現と相関していた。IgAの発現は、一部の腸内細菌の変動と相関していた。令和3年度は、CNS内でのIgA発現に関わる因子の研究を進めた。IgAは粘膜免疫の主役であり、この誘導には、腸管粘膜の細菌叢が重要な役割を果たす。我々は、腸内細菌の産生する因子の中で、リピド A がIgA産生の誘導することが報告されているため、IgAのマウスへの投与を行った。IgA投与により、TMEV投与群では、臨床症状に変化が認められ、この臨床症状の軽減は腸内細菌叢のAlistipes属とMuribaculaceae (S24-7)科の細菌の変動に関連していた。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/06 -2022/03 
    Author : Nishio Kazuto
     
    Host-microbe interactions in inflammatory bowel disease were investigated. Activation of ribonucleoprotein complex biosynthesis and cytokine signaling pathway mediated by the gut microbiota affected DNA repair, IFN-γ signaling, etc. in the colonic mucosa and was associated with response to immune checkpoint inhibitors and immune-related colitis. Immune checkpoint inhibitor-induced immune-associated colitis showed functional similarities in gut tissue and microbial composition with ulcerative colitis, but decreased Bacteroides species resulted in an enhanced fatty acid transport system and immune cell reorganization in both diseases. The gut microbiota is involved in pathogenesis of multiple sclerosis and curcumin monoglucuronide modulated microbiota and the pathogenesis histologically.
  • 日本医療研究開発機構(AMED):新興・再興感染症に対する革新的医薬品等開発推進研究事業
    Date (from‐to) : 2019/04 -2022/03 
    Author : 角田郁生
  • 日本医療研究開発機構(AMED):新興・再興感染症に対する革新的医薬品等開発推進研究事業
    Date (from‐to) : 2020/05 -2021/03 
    Author : 森田英嗣; 角田郁生; 田中伸幸; 蝦名博貴
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up
    Date (from‐to) : 2016/08 -2018/03 
    Author : TSUNODA Ikuo; OMURA Seiichi
     
    In mulitple sclerosis (MS), it has been proposed that IL-17-producing T helper (Th)17 cells are detrimental, and regulatory T cells (Tregs) are protective. Using a viral model for MS, Theiler's murine encephalomyelitits virus (TMEV)-induced demyelinating disease (TMEV-IDD), we aimed to clarify the roles of Th17 cells and Tregs. Using methods to increase the numbers of Th17 cells or Tregs ("gain-of-function" approach), we found that Th17 cells have three roles: 1) exacerbation of inflammation, 2) suppression of anti-viral immunity, and 3) neuroprotection and that Tregs have two roles: 1) suppression of inflammation and 2) suppression of anti-viral immunity. Therefore, Th17 cells and Tregs may play either beneficial or detrimental roles in MS, depending on the causes or disease course. These findings can be used for future tailor-made treatment of MS, in which Th17 cells and Tregs should be modulated depending on the conditions of patients with MS.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : PARK Ah-Mee; TSUNODA Ikuo
     
    The purpose of this study is to clarify the role of Galectin-3 (Gal3) on NSAIDs-induced intestinal ulcer. By using Gal3 knockout mice, we found that Gal-3 is a worsen factor of NSAIDs-induced intestinal ulcer. There are two possible mechanism for this negative effect of Gal3. The first one is a role of Gal3 as danger signal of activated macrophages. This molecule might cause sever inflammation. The another one is changes of intestinal bacterial flora with or without Gal-3. We found obvious differences of small intestinal flora population between wildtype mice and Gal3 mice. Those differences might affect to the ulceration by NSAIDs.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : YOSHIE Osamu; NAKAYAMA Takashi; TSUNODA Ikuo
     
    CCL28 is expressed in the mucosal tissues and to attract IgA-antibody secreting cells (IgA-ASCs) via CCR10. CCL28 has an antimicrobial activity against microbes in vitro. However, in vivo evidence for the role of CCL28 in the mucosal immunity remains scanty. We generated CCL28-deficient mice and demonstrated that CCL28-deficient mice showed reduced numbers and altered distribution of IgA-ASCs in the colon. The IgA contents in the fecal extracts were low. The average amounts of IgA secreted by a single IgA-ASC isolated from the lamina propria of the colon was reduced. Furthermore, the 16S rRNA sequencing analysis of feces revealed an increase of the Class Bacilli. Consistent with the low IgA production and altered microbiota in the colon, CCL28-deficient mice had aggravated colitis upon treatment with dextran sulfate, which was ameliorated by oral antibiotics. Therefore, CCL28 has an role in the mucosal immunity of the colon as a chemoattractant with a direct antimicrobial activity.
  • Animal models for multiple sclerosis
    Louisiana State University Health Sciences Center (LSUHSC):Neurology Research Grant
    Date (from‐to) : 2015 -2016 
    Author : Ikuo Tsunoda
  • NIH/National Institute of General Medical Sciences (NIGMS):Centers of Biomedical Research Excellence (COBRE) III Pilot Grant
    Date (from‐to) : 2014 -2016 
    Author : Ikuo Tsunoda
  • Neurotropic viral model
    Louisiana State University Health Sciences Center (LSUHSC):Research Development Funds
    Date (from‐to) : 2013 -2014 
    Author : Ikuo Tsunoda
  • Neuroprotective Role of Glatiramer Acetate in a Viral Model for Multiple Sclerosis
    TEVA Neuroscience:Investigator-Initiated Studies Program
    Date (from‐to) : 2012 -2014 
    Author : Ikuo Tsunoda
  • Systems Biology Approach for Molecular Mechanisms in Viral Myocarditis
    Malcolm Feist Cardiovascular Foundation:Malcolm Feist Cardiovascular Research Fellowship
    Date (from‐to) : 2011 -2014 
    Author : Seiichi Omura; Ikuo Tsunoda
  • Regulatory Role of Natural Killer T cells in Cardiovirus-induced Myocarditis
    Malcolm Feist Cardiovascular Foundation:Malcolm Feist Cardiovascular Research Fellowship
    Date (from‐to) : 2011 -2014 
    Author : Fumitaka Sato; Ikuo Tsunoda
  • Th Cells in Theiler’s Virus Persistence and Pathology
    NIH/National Center for Research Resources (NCRR) and National Institute of General Medical Sciences (NINGS):Centers of Biomedical Research Excellence (COBRE) II
    Date (from‐to) : 2010 -2014 
    Author : Ikuo Tsunoda
  • NeuroVirology and Neuroimmunology Animal Models
    Louisiana State University Health Sciences Center (LSIHSC):Research Council Seed Package
    Date (from‐to) : 2009 -2012 
    Author : Ikuo Tsunoda
  • Axonal Degeneration can Trigger Demyelinating Disease
    National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS):R21
    Date (from‐to) : 2008 -2011 
    Author : Ikuo Tsunoda
  • Treatment of Animal Models for MS with Resveratrol, a Natural Compound in Red Wine
    National Multiple Sclerosis Society (NMSS):Pilot Research Award
    Date (from‐to) : 2008 -2009 
    Author : Ikuo Tsunoda
  • Does Axonal Injury Recruit Inflammatory Cells to the Site of Axonal Degeneration, Targeting Demyelinating Lesions? Inside-Out Model for Multiple Sclerosis.
    University of Utah:The Funding Incentive Seed Grant
    Date (from‐to) : 2006 -2008 
    Author : Ikuo Tsunoda
  • Immunologic Factors In Progressive Autoimmune Disease
    National Institute of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS):R01
    Date (from‐to) : 2002/07 -2006/06 
    Author : Robert S. Fujinami; Ikuo Tsunoda
     
    Multiple sclerosis (MS) can be divided into four clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR). The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW. We induce experimental allergic encephalomyelitis (EAE) with (MOG)92-106 in the presence or absence of supplemental Bordetella pertussis (BP). SJL/J mice develop RR-EAE whether BP was administered or not. Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation. Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice. We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival. To test this hypothesis, four specific aims are proposed. The first aim will study the role of NK1.1+ T cells in progressive disease. The second aim will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with (MOG)92-106. The third aim will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation. The fourth and last aim will study other factors involved in progressive disease such as environmental and genetic contributions. These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.
  • Lesion development from inside (axon) to outside (myelin): Inside-Out models
    National Multiple Sclerosis Society (NMSS):Pilot Research Award
    Date (from‐to) : 2004 -2005 
    Author : Ikuo Tsunoda
  • Viral and Cellular Deteminants Involved in CNS Disease
    National Institute of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS):R01
    Date (from‐to) : 1995 -2005 
    Author : Robert S. Fujinami; Ikuo Tsunoda
     
    Theiler's murine encephalomyelitis virus (TMBV) infection of mice is a relevant animal model for the human demyelinating disease multiple sclerosis (MS). TMEV belongs to the Picornaviridae family and are in the Cardiovirus genus. These viruses are small positive-sense single-stranded RNA viruses. Infection of mice with the DA strain of TMEV causes an acute polioencephalomyelitis where mice survive and later develop a central nervous system (CNS) inflammatory demyelinating disease. Once clinical signs (weight loss, spastic paralysis and gait disturbances) develop in these mice, there is disease progression without relapses or remissions. This mirrors the progressive forms of MS. Many reports have described the need for CD8+ and CD4+ T cells as well as antibodies in the pathogenesis of TMEV induced demyelinating disease. CD8+ T cells have been reported to be responsible for viral clearance and protection from the chronic demyelinating disease in resistant mice. Similarly, CD4+ T cells have been described to be responsible for the inflammatory CNS demyelination in infected susceptible mice. Recently, CD8+ T cells have also been shown to influence demyelination in DA virus infected mice. We have evidence that another cell type may also participate in TMEV infection and demyelinating disease. This new cell type has cytotoxic activity on uninfected syngenic target cells but not allogenic target cells. In preliminary studies, the cell is CD3+, CD8+ and B22O+ and can cause inflammation in the CNS. These cells are induced by TMEV infection but not vaccinia virus infection of susceptible SJL/J. The goals of this application are to: 1) further characterize the phenotype of the autoreactive killer cells; 2) determine how these cells contribute to disease and define the mechanism of killing; 3) study the induction of the killer cells; and 4) define the determinant(s) in VP1 necessary for the induction of the autoreactive cells. These findings are novel and may help explain differences between various reports stating that CD4+ or CD8+ T cells are exclusively involved in demyelination and viral clearance, respectively. The studies not only are important to viral pathogenesis but also the pathogenesis of autoimmune disease.
  • Viruses and Autoimmunity ot the Central Nervous System
    National Institute of Health (NIH) / National Institute of Allergy and Infectious Diseases (NIAID):R01
    Date (from‐to) : 2004 
    Author : Robert S. Fujinami; Ikuo Tsunoda
     
    Most evidence suggests that multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). It is the most common human demyelinating disease. Immune mediated events are involved in the etiology and pathogenesis. Therefore, myelin specific autoreactive T cells are believed to mediate the inflammatory demyelination. In this disease viral infections are associated with initiation and/or exacerbations. Epidemiologic studies indicate that where one lives their first 15 years of life help determines whether one acquires a high or low MS risk phenotype. These data suggest that infections early in life confer a risk or primes individuals for autoimmune disease that originates later in life. Reports show approximately 30% of MS exacerbations (attacks) is preceded by viral infections. While no one infectious agent has been demonstrated to be etiologic agent for MS, there is ample evidence pointing towards viral infections being involved in the initiation and later triggering attacks of disease. We have established an animal model for MS where a viral infection early in life can prime them for exacerbations later in life. The exacerbation is induced by a different viral infection than the first. In our model the first infection has molecular mimicry with a CNS protein(s). We have made a recombinant vaccinia virus (VV) that encodes myelin proteolipid protein (PLP). This initial infection (VV-PLP) does not appear to incite CNS disease by itself. However, when we challenge VV-PLP primed animals with murine cytomegalovirus (MCMV), animals develop inflammatory CNS lesions. The second or challenge infection could induce disease by two mechanisms that are not mutually exclusive: 1) The second infection activates already primed autoreactive T cells by bystander activation, and in sufficient numbers, these T cells would migrate into the CNS and initiate disease; and 2) MCMV could have a cross-reactive epitope with PLP presented by activated dendritic cells to primed autoreactive T cells leading to inflammatory CNS disease. We propose to investigate the immunological basis for the initiation or priming phase and the later challenge phase of inflammatory CNS disease. Our model could provide an explanation why no single microbe has been identified as the MS agent but is likely to be a combination of infectious events.

Teaching Experience

  • Medical EnglishMedical English Kindai University, Faculty of Medicine
  • Introduction to ResearchIntroduction to Research Louisiana State University
  • Foundations of Biomedical Sciences: Nervous SystemFoundations of Biomedical Sciences: Nervous System Louisiana State University
  • ImmunologyImmunology Louisiana State University
  • Pathogenesis of Infectious DiseasesPathogenesis of Infectious Diseases Louisiana State University
  • General and Molecular VirologyGeneral and Molecular Virology Louisiana State University
  • Microbiology & Infectious DiseasesMicrobiology & Infectious Diseases Louisiana State University

Committee Membership

  • 2022 - Today   JAPANESE SOCIETY OF PATHOPHYSIOLOGY   Councilor
  • 2020/04 - Today   The Japanese Society for Virology   Councilor
  • 2015 - Today   National Institutes of Health (NIH), Centers of Biomedical Research Excellence (COBRE)   Reviewer, COBRE Small Grants Program P30GM114737. University of Hawaii
  • 2015 -2016   Swiss Multiple Sclerosis Society   Reviewer, Project Grant
  • 2016   Florida Department of Health   Reviewer, Zika Research Grant Initiative
  • 2014   Multiple Sclerosis Society, UK   Reviewer, Project Grant
  • 2010 -2013   The Italian Multiple Sclerosis Society   Reviewer, AISM-FISM
  • 2013   The Department of Veterans Affairs   Study Section Reviewer, Neurobiology-B (NURB) Scientific Review Group
  • 2010   The Italian Ministry of Health   Reviewer, Research Funding Call Grant 2009
  • 2010   The National Multiple Sclerosis Society   Ad Hoc Reviewer NMSS, Pilot Research Award
  • 2005 -2009   Ad Hoc Merit Grant Reviewer   The Salt Lake VA Research and Development Committee

Media Coverage

Academic Contribution

  • Walk MS Shreveport Team Leader
    Date (from-to) :2011-2015
    Role: Planning etc
    Organizer, responsible person: National Multiple Sclerosis Society (NMSS), Louisiana

Others

  • 2021/07 -2022/03  令和3年度“オール近大”新型コロナウイルス感染症 対策支援プロジェクト研究: 腸内細菌因子による新型コロナウイルス粘膜免疫の増強 (研究17) 
    新型コロナウイルス (SARS-CoV-2) はプラス鎖 (+) 一本鎖 RNA をゲノムとして持つ RNA ウイルスで、呼吸器粘膜上皮に感染することで肺炎をきたす。SARS-CoV-2 の感染予防を目的にワクチンが開発されたが、既存のワクチンは皮下・筋肉内投与であるため、血中には主に抗ウイルス IgG 抗体が誘導される。しかし、呼吸器・腸管などの粘膜部位における感染防御の主体は IgA 抗体であり、IgG 抗体ではない。それゆえに、呼吸器粘膜に抗ウイルス IgA 抗体を誘導するワクチンの開発が、より効果的な SARS-CoV-2 感染予防には望まれる。そこで本研究では、IgA 誘導の効率を高めるため、IgA 産生を安全かつ強力に増加させることができるアジュバント (腸内細菌由来因子) を使用することで、IgA 抗体の誘導効率の向上を目的とする。また、SARS-CoV-2 は、呼吸器だけでなく中枢神経系 (central nervous system: CNS) にも感染したり、感染に伴いギランバレー症候群を誘導するなどの、神経系の病態により、重篤な転機となることも示唆されている。そこで本研究では、マウスCNSウイルス感染モデルを用いて、IgA がウイルスのCNS 感染防御において果たす役割を解明する。
  • 2020/07 -2021/03  “All Kindai” COVID-19 Support Project, Research 11, 2020-2021. Role of Anti-Viral IgA Antibody in COVID-19. 
    3,500,0000 yen. (Tsunoda is PI).

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