MATSUO Kazuhiko

Researcher Information

Degree

• PhD（2011/03 Osaka University）

URL

http://kaken.nii.ac.jp/d/r/70615921.ja.html

Research funding number

• 70615921

J-Global ID

• 201401059508779871

Research Interests

• 免疫記憶   ワクチンアジュバント   ケモカイン   自己溶解型マイクロニードル   経皮ワクチン   アルツハイマー病   

Research Areas

• Life sciences / Infectious disease
• Life sciences / Clinical pharmacy

Academic & Professional Experience

• 2023/04 - Today  Kindai UniversityFaculty of Pharmacy Department of Pharmacy准教授
• 2017/04 - 2023/03  Kindai UniversityFaculty of Pharmacy, Department of Pharmacy講師
• 2012/04 - 2017/03  Kindai UniversityFaculty of Pharmacy, Department of Pharmacy助教
• 2011/04 - 2012/03  Osaka University薬学研究科(研究院)特任研究員

Published Papers

• Aggravation of lipopolysaccharide-induced depressive-like behavior in CCR4-deficient mice

  Yuta Hara; Tatsuma Honzawa; Moeka Kitagawa; Ritsuki Sano; Kazuhiko Matsuo; Takashi Nakayama

  Journal of Pharmacological Sciences Elsevier BV 153 (3) 89 - 93 1347-8613 2023/11
• A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells

  Masako Sato; Kazuhiko Matsuo; Yoko Susami; Ayaka Yamashita; Haruko Hayasaka; Yuta Hara; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama

  International Immunology Oxford University Press (OUP) 35 (9) 437 - 446 2023/06 

  Abstract CCR4 is a major trafficking receptor for Th2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, Thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c + dendritic cells and CD4 + T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.
• EBV-positive pyothorax-associated lymphoma expresses CXCL9 and CXCL10 chemokines that attract cytotoxic lymphocytes via CXCR3.

  Tomonori Higuchi; Yumiko Hashida; Kazuhiko Matsuo; Kosuke Kitahata; Takako Ujihara; Ichiro Murakami; Takashi Nakayama; Masanori Daibata

  Cancer science 114 (6) 2622 - 2633 2023/03 

  Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) develops in the setting of long-standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL-CI. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C-X-C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV-negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3-expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3-positive cytotoxic lymphocytes that expressed interferon-γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3-positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.
• A spatially resolved atlas of the human lung characterizes a gland-associated immune niche.

  Elo Madissoon; Amanda J Oliver; Vitalii Kleshchevnikov; Anna Wilbrey-Clark; Krzysztof Polanski; Nathan Richoz; Ana Ribeiro Orsi; Lira Mamanova; Liam Bolt; Rasa Elmentaite; J Patrick Pett; Ni Huang; Chuan Xu; Peng He; Monika Dabrowska; Sophie Pritchard; Liz Tuck; Elena Prigmore; Shani Perera; Andrew Knights; Agnes Oszlanczi; Adam Hunter; Sara F Vieira; Minal Patel; Rik G H Lindeboom; Lia S Campos; Kazuhiko Matsuo; Takashi Nakayama; Masahiro Yoshida; Kaylee B Worlock; Marko Z Nikolić; Nikitas Georgakopoulos; Krishnaa T Mahbubani; Kourosh Saeb-Parsy; Omer Ali Bayraktar; Menna R Clatworthy; Oliver Stegle; Natsuhiko Kumasaka; Sarah A Teichmann; Kerstin B Meyer

  Nature genetics 55 (1) 66 - 77 2023/01 

  Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.
• CCR4 plays a pivotal role in Th17 cell recruitment and expansion in a mouse model of rheumatoid arthritis.

  Tatsuma Honzawa; Kazuhiko Matsuo; Shunya Hosokawa; Mayu Kamimura; Yuichiro Kaibori; Yuta Hara; Daisuke Nagakubo; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Osamu Yoshie; Takashi Nakayama

  International immunology 34 (12) 635 - 642 2022/08 

  Th17 cells express CCR4 and secrete cytokines such as IL-17A and GM-CSF, while dendritic cells (DCs) produce CCL22, a CCR4 ligand, upon stimulation with GM-CSF. Th17 cells are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). CCL22 has also been shown to be upregulated in the synovial tissues of RA patients. Here, we investigated the role of CCR4 in collagen-induced arthritis (CIA), a mouse model of RA. DBA/1J mice efficiently developed CIA as shown by erythema, paw swelling, joint rigidity, and joint destruction. Th17 cells were increased in the arthritic joints and regional lymph nodes (LNs) of CIA mice. A fraction of Th17 cells were also shown to produce GM-CSF. On the other hand, we observed no significant increases of Th2 cells or Treg cells, the T cell subsets also known to express CCR4, in these tissues. We further observed clusters of CCR4-expressing memory Th17 cells and CCL22-producing DCs in the regional LNs of CIA mice, supporting the role of the CCR4-CCL22 axis in the expansion of Th17 cells in the regional LNs. Compound 22, a CCR4 inhibitor, ameliorated the disease severity with reduction of Th17 cells in the arthritic joints and regional LNs and Th17-DC clusters in the regional LNs. We further confirmed that CCR4-deficient mice in the C57BL/6J background were highly resistant to CIA induction compared with wild-type mice. Collectively, CCR4 contributes to the pathogenesis of CIA and may thus represent a new therapeutic target for RA.
• Anti-allergic effect of ascorbic acid derivative DDH-1 in a mouse model of atopic dermatitis.

  Kosuke Kitahata; Kazuhiko Matsuo; Masako Sato; Yoko Susami; Yuta Hara; Toshio Morikawa; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama

  Experimental dermatology 31 (8) 1234 - 1242 2022/04 

  Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.
• Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity.

  Kazuhiko Matsuo; Osamu Yoshie; Takashi Nakayama

  Cancers 13 (23) 2021/12 

  Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.
• Commensal bacteria promote type I interferon signaling to maintain immune tolerance

  Adriana Vasquez Ayala; Chia-Yun Hsu; Kazuhiko Matsuo; Ekaterina Buzun; Marvic Carrillo Terrazas; Luke R. Loomis; Hsueh-Han Lu; Jong Hwee Park; Paul Rivaud; Matt Thomson; Hiutung Chu

  Cold Spring Harbor Laboratory 2021/10 

  ABSTRACT Type I interferons (IFN) exert a broad range of biological effects important in coordinating immune responses. Host and microbial factors regulate IFN production, triggering a signaling cascade that has classically been studied in the context of pathogen clearance. In particular, commensal bacteria have been shown to induce IFN to protect against viral infections. Yet, whether immunomodulatory bacteria operate through IFN pathways to support immune tolerance remains elusive. Here, we demonstrate microbiota-dependent IFN signaling is required for priming tolerogenic T regulatory cells (Tregs) by intestinal dendritic cells (DCs). DCs deficient in IFN signaling through deletion of IFNAR-1 display dysregulated cytokine production in response to the commensal bacteria Bacteroides fragilis, resulting in blunted downstream Treg responses. Single cell RNA sequencing of gut tissues demonstrated that colonization with B. fragilis promotes a distinct type I IFN gene signature in Tregs during homeostasis and intestinal inflammation. Moreover, B. fragilis-mediated protection during experimental colitis was abrogated in IFNAR1-deficient mice. Altogether, our findings demonstrate an important role of microbiota-mediated immune tolerance via tonic type I IFN signaling.
• 乾癬におけるケモカイン受容体CCR4を介したTh17細胞の遊走制御機構と病理的役割

  松尾 一彦; 北畑 孝祐; 中山 隆志

  アレルギーの臨床 (株)北隆館 41 (11) 1018 - 1022 0285-6379 2021/10 

  ケモカイン受容体CCR4はTh2細胞とTh17細胞の主要な細胞遊走因子受容体である。CCR4はアレルギー性疾患などのTh2関連疾患において重要な役割を果たすが、乾癬などのTh17関連疾患における役割についてはほとんど不明である。本稿では、乾癬におけるCCR4を介したTh17細胞の局在制御機構とその病態発症における役割について、著者らの研究成果を交えて最新の知見を紹介する。(著者抄録)
• CCR4 Involvement in the Expansion of T Helper Type 17 Cells in a Mouse Model of Psoriasis.

  Kazuhiko Matsuo; Kosuke Kitahata; Yuichiro Kaibori; Yuka Arima; Arisa Iwama; Mana Ito; Yuta Hara; Daisuke Nagakubo; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  The Journal of investigative dermatology 141 (8) 1985 - 1994 2021/08 

  Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice. Th17 cells were decreased in the skin lesions and regional lymph nodes of CCR4-deficient mice. In the regional lymph nodes of wild-type mice, CD44+ memory Th17 cells expressing CCR4 were found to be clustered with dendritic cells expressing CCL22, a ligand for CCR4. Such dendritic cell‒Th17 cell clusters were significantly decreased in CCR4-deficient mice. Similar results were obtained using the IL-23‒induced psoriasis model. In vitro, compound 22, a CCR4 antagonist, significantly reduced the expansion of Th17 cells in the coculture of CD11c+ dendritic cells and CD4+ T cells separately prepared from the regional lymph nodes of wild-type mice with psoriasis. In vivo, compound 22 ameliorated the psoriasis-like skin disease in wild-type mice with significant decreases of Th17 cells in the regional lymph nodes and skin lesions. Collectively, CCR4 is likely to play a role in the pathogenesis of psoriasis through the expansion of Th17 cells.
• Recent Progress in Dendritic Cell-Based Cancer Immunotherapy.

  Kazuhiko Matsuo; Osamu Yoshie; Kosuke Kitahata; Momo Kamei; Yuta Hara; Takashi Nakayama

  Cancers 13 (10) 2021/05 

  Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.
• 乾癬におけるTh17細胞増殖に対するケモカイン受容体CCR4の役割

  松尾 一彦; 北畑 孝祐; 中山 隆志

  別冊Bio Clinica: 慢性炎症と疾患 (株)北隆館 10 (1) 132 - 136 2021/05 

  ケモカイン受容体CCR4はTh2細胞とTh17細胞の主要な細胞遊走因子受容体である。CCR4はアレルギー性疾患などのTh2関連疾患において重要な役割を果たすが、乾癬などのTh17関連疾患における役割についてはほとんど不明である。本稿では、乾癬におけるCCR4を介したTh17細胞の局在制御機構とその病態発症における役割について、著者らの研究成果を交えて最新の知見を紹介する。(著者抄録)
• P2X receptor agonist enhances tumor-specific CTL responses through CD70 + DC-mediated Th17 induction.

  Shinya Yamamoto; Kazuhiko Matsuo; Sho Sakai; Itsuki Mishima; Yuta Hara; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  International immunology 33 (1) 49 - 55 2020/10 

  Extracellular ATP is known to promote Th17 cell differentiation in the intestinal lamina propria by stimulating CD70 +CD11c low dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that Th17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, αβ-methylene ATP (αβ-ATP), as a mucosal vaccine adjuvant to promote CTL responses through Th17 induction. We demonstrated that (1) CD70 +CD11c low DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (2) CD70 +CD11c low DCs isolated from the nasal lamina propria enhanced Th17 cell differentiation of cocultured splenic CD4 + T cells upon stimulation with αβ-ATP; (3) mice intranasally immunized with ovalbumin (OVA) and αβ-ATP had increased OVA-specific Th17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (4) mice intranasally immunized with OVA and αβ-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (5) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific Th17 cells and CTLs in mice intranasally immunized with OVA and αβ-ATP; (6) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and αβ-ATP against E.G7-OVA. Collectively, αβ-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70 +CD11c low DC-mediated Th17 induction.
• Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury.

  Ryota Sakai; Minako Ito; Kyoko Komai; Mana Iizuka-Koga; Kazuhiko Matsuo; Takashi Nakayama; Osamu Yoshie; Koichi Amano; Hiroshi Nishimasu; Osamu Nureki; Masato Kubo; Akihiko Yoshimura

  Cellular & molecular immunology 18 (5) 1249 - 1261 2020/09 

  FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30-35% of CD4+ T cells) during the late stage (days 21-90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.
• Transcutaneous immunization with a highly active form of XCL1 as a vaccine adjuvant using a hydrophilic gel patch elicits long-term CD8+ T cell responses

  Momo Kamei; Kazuhiko Matsuo; Haruka Imanishi; Yuta Hara; Ying-Shu Quen; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Naoki Okada; Takashi Nakayama

  J. Pharmacol. Sci. Elsevier BV 143 (3) 182 - 187 1347-8613 2020/07 [Refereed]
   

  Memory CD8+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses.
• 【乾癬治療の最前線】乾癬病態形成におけるケモカイン系の役割

  松尾 一彦; 中山 隆志

  ファルマシア (公社)日本薬学会 56 (4) 309 - 313 0014-8601 2020/04 

  ケモカインは細胞遊走活性を有するサイトカインの一群であり，免疫細胞の遊走制御を介して生体内における免疫システムの形成および恒常性維持に関与している．また，病的状況下においては様々なケモカインの異所性発現が見られ，それによって起こる免疫細胞遊走の異常が病態形成に密接に関わっている．
  本稿では，乾癬発症に重要な役割を果たすヘルパーT細胞サブセットであるTh17細胞とケモカイン系の役割について，著者らの研究成果を交えて紹介する．
• Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung.

  Shiki Takamura; Shigeki Kato; Chihiro Motozono; Takeshi Shimaoka; Satoshi Ueha; Kazuhiko Matsuo; Kosuke Miyauchi; Tomoko Masumoto; Asami Katsushima; Takashi Nakayama; Michio Tomura; Kouji Matsushima; Masato Kubo; Masaaki Miyazawa

  The Journal of experimental medicine 216 (12) 2736 - 2747 0022-1007 2019/12 [Refereed]
   

  Populations of CD8+ lung-resident memory T (TRM) cells persist in the interstitium and epithelium (airways) following recovery from respiratory virus infections. While it is clear that CD8+ TRM cells in the airways are dynamically maintained via the continuous recruitment of new cells, there is a vigorous debate about whether tissue-circulating effector memory T (TEM) cells are the source of these newly recruited cells. Here we definitively demonstrate that CD8+ TRM cells in the lung airways are not derived from TEM cells in the circulation, but are seeded continuously by TRM cells from the lung interstitium. This process is driven by CXCR6 that is expressed uniquely on TRM cells but not TEM cells. We further demonstrate that the lung interstitium CD8+ TRM cell population is also maintained independently of TEM cells via a homeostatic proliferation mechanism. Taken together, these data show that lung memory CD8+ TRM cells in the lung interstitium and airways are compartmentally separated from TEM cells and clarify the mechanisms underlying their maintenance.
• Epstein-Barr virus-positive pyothorax-associated lymphoma expresses CCL17 and CCL22 chemokines that attract CCR4-expressing regulatory T cells.

  Higuchi T; Matsuo K; Hashida Y; Kitahata K; Ujihara T; Taniguchi A; Yoshie O; Nakayama T; Daibata M

  Cancer letters 453 184 - 192 0304-3835 2019/07 [Refereed]
   

  Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas associated with chronic inflammation (DLBCL-CI) develop in patients with chronic inflammation but without any predisposing immunodeficiency. Given the expression of the EBV latent genes, DLBCL-CI should have mechanisms for evasion of host antitumor immunity. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and may provide a valuable model for the study of immune evasion by DLBCL-CI. This study demonstrates that PAL cell lines express and secrete CCL17 and/or CCL22 chemokines, the ligands of C-C motif chemokine receptor 4 (CCR4), in contrast to EBV-negative DLBCL cell lines. Accordingly, culture supernatants of PAL cell lines efficiently attracted CCR4-positive regulatory T (Treg) cells in human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CCR4-expressing Treg cells. Furthermore, this study confirmed that CCR4-expressing Treg cells were abundantly present in primary PAL tissues. Collectively, these findings provide new insight into the mechanisms of immune evasion by PAL, and further studies are warranted on whether such mechanisms eventually lead to the development of DLBCL-CI.
• A CCR4 antagonist ameliorates atopic dermatitis-like skin lesions induced by dibutyl phthalate and a hydrogel patch containing ovalbumin.

  Kazuhiko Matsuo; Shota Hatanaka; Yuta Kimura; Yuta Hara; Keiji Nishiwaki; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Kenji Kabashima; Takashi Nakayama

  Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 109 1437 - 1444 0753-3322 2019/01 [Refereed]
   

  CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.
• Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery.

  Ito M; Komai K; Mise-Omata S; Iizuka-Koga M; Noguchi Y; Kondo T; Sakai R; Matsuo K; Nakayama T; Yoshie O; Nakatsukasa H; Chikuma S; Shichita T; Yoshimura A

  Nature 565 (7738) 246 - 250 0028-0836 2019/01 [Refereed]
   

  In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3-5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.
• Ascorbic acid derivative DDH-1 ameliorates psoriasis-like skin lesions in mice by suppressing inflammatory cytokine expression.

  Kosuke Kitahata; Kazuhiko Matsuo; Yuta Hara; Takanori Naganuma; Naoki Oiso; Akira Kawada; Takashi Nakayama

  Journal of pharmacological sciences 138 (4) 284 - 288 1347-8613 2018/12 [Refereed]
   

  Psoriasis is a chronic inflammatory skin disease in which inflammatory cytokines play a major role in its pathogenesis. Because DDH-1, a novel amphipathic ascorbic acid derivative, has been recently shown to reduce inflammatory cytokine expression in human keratinocytes in vitro, we investigated its effect on imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice. We first found that IL-1β and TNF-α mRNA expression was significantly decreased in the skin lesions treated with DDH-1. Furthermore, cutaneous administration of DDH-1 ameliorated psoriasis-like skin lesions. These results suggest that DDH-1 may be effective in the prevention and supplemental treatment of psoriasis.
• CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice.

  Kazuhiko Matsuo; Daisuke Nagakubo; Yuhei Komori; Shun Fujisato; Natsumi Takeda; Mizuki Kitamatsu; Keiji Nishiwaki; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  The Journal of investigative dermatology 138 (8) 1764 - 1773 0022-202X 2018/08 [Refereed]
   

  Atopic dermatitis is a chronic inflammatory skin disease involving T-helper (Th) 2 cells, eosinophils, and mast cells. Although CCR4 is a major chemokine receptor expressed on Th2 cells and regarded as a potential therapeutic target for allergic diseases, its role in atopic dermatitis remains unclear. Here, by using a hydrogel patch as a transcutaneous delivery device for ovalbumin (an antigen) and Staphylococcus aureus δ-toxin (a mast cell activator), we efficiently induced acute atopic dermatitis-like skin lesions in BALB/c mice, a strain prone to Th2 responses, which were characterized by increased numbers of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions; elevated levels of total and ovalbumin-specific IgE in the sera; and increased expression of IL-4, IL-17A, IL-22, CCL17, CCL22, and CCR4 in the skin lesions. Of note, the same model was less efficient in C57BL/6 mice, a strain prone to Th1 responses. Using this atopic dermatitis model in BALB/c mice, we demonstrated that CCR4-deficiency or a CCR4 antagonist ameliorated the allergic responses. Collectively, these results demonstrate that CCR4 plays a pivotal role in skin allergic inflammation of BALB/c mice by recruiting CCR4-expressing Th2 cells and Th17 cells.
• A CCR4 antagonist enhances DC activation and homing to the regional lymph node and shows potent vaccine adjuvant activity through the inhibition of regulatory T-cell recruitment.

  Shinya Yamamoto; Kazuhiko Matsuo; Daisuke Nagakubo; Shintaro Higashiyama; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  Journal of pharmacological sciences 136 (3) 165 - 171 1347-8613 2018/03 [Refereed]
   

  CCR4 is a major chemokine receptor expressed by Treg cells that downregulate immune responses. Here, we investigated the role of CCR4-mediated Treg cell recruitment in antigen-specific immune responses. CCR4-deficient mice immunized intramuscularly with ovalbumin (OVA) showed enhanced OVA-specific IgG responses. Furthermore, intramuscular administration of OVA induced the expression of MDC/CCL22, a ligand for CCR4, in macrophages of the muscle tissues, and enhanced the recruitment of CCR4+ Treg cells in wild-type mice, whereas this recruitment of Treg cells was severely impaired in CCR4-deficient mice. Furthermore, OVA-loaded dendritic cells (DCs) derived from the muscle injection site of CCR4-deficient mice had an upregulated expression of the DC activation marker CD40 and 86, and the lymphoid organ homing receptor CCR7 resulting in an increased number of migratory DCs in the regional lymph node. Compound 22, a CCR4 antagonist, also inhibited the recruitment of Treg cells to the muscle tissue, and further enhanced DC activation and homing to the regional lymph node. Consequently, Compound 22 enhanced OVA-specific IgG responses, and the expression levels of IL-4 and IFN-γ in CD4+ T cells and the levels of IFN-γ in CD8+ T cells. Finally, intramuscular administration of OVA and Compound 22 significantly inhibited the growth of OVA-expressing tumors. Collectively, CCR4 plays a pivotal role in Treg cell recruitment to the muscle tissue, and intramuscular administration of CCR4 antagonists may be a promising approach for enhancing vaccine efficacy.
• CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon.

  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.
• A Highly Active Form of XCL1/Lymphotactin Functions as an Effective Adjuvant to Recruit Cross-Presenting Dendritic Cells for Induction of Effector and Memory CD8+ T Cells.

  Kazuhiko Matsuo; Kosuke Kitahata; Fumika Kawabata; Momo Kamei; Yuta Hara; Shiki Takamura; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  Frontiers in immunology 9 2775 - 2775 2018 [Refereed]
   

  The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8+ T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8+ T cell responses by preferentially delivering antigens to XCR1+ DCs. However, XCL1 per se was found to be a poor adjuvant for induction of CD8+ T cell responses. XCL1 is unique because of its lack of one of the two disulfide bonds commonly conserved in all other chemokines and thus has an unstable structure with a relatively weak chemokine activity. In the present study, we generated a variant form of murine XCL1 termed mXCL1-V21C/A59C that contained a second disulfide bond to stabilize its chemokine structure. We confirmed that mXCL1-V21C/A59C had much more potent chemotactic and calcium mobilization activities than the wild type XCL1 (mXCL1-WT). Intradermal injection of mXCL1-V21C/A59C, but not that of mXCL1-WT, significantly increased the accumulation of XCR1+CD103+ DCs in the injection site, and most of the accumulated XCR1+CD103+ DCs were found to take up co-injected ovalbumin (OVA). Furthermore, recruited XCR1+CD103+ DCs efficiently migrated to the draining lymph nodes and stayed for a prolonged period of time. Consequently, mXCL1-V21C/A59C strongly induced OVA-specific CD8+ T cells. The combination of OVA and mXCL1-V21C/A59C well protected mice from E.G7-OVA tumor growth in both prophylactic and therapeutic protocols. Finally, memory CTL responses were efficiently induced in mice immunized with OVA and mXCL1-V21C/A59C. Although intradermal injection of OVA and polyinosinic-polycytidylic acid (poly(I:C)) as an adjuvant also induced CD8+ T cell responses to OVA, poly (I:C) poorly recruited XCR1+CD103+ DCs in the injection site and failed to induce significant memory CTL responses to OVA. Collectively, our findings demonstrate that a highly active form of XCL1 is a promising vaccine adjuvant for cross-presenting DCs to induce antigen-specific effector and memory CD8+ T cells.
• Impaired lymphocyte trafficking in mice deficient in the kinase activity of PKN1

  Rana Mashud; Akira Nomachi; Akihide Hayakawa; Koji Kubouchi; Sally Danno; Takako Hirata; Kazuhiko Matsuo; Takashi Nakayama; Ryosuke Satoh; Reiko Sugiura; Manabu Abe; Kenji Sakimura; Shigeharu Wakana; Hiroyuki Ohsaki; Shingo Kamoshida; Hideyuki Mukai

  SCIENTIFIC REPORTS NATURE PUBLISHING GROUP 7 (1) 7663  2045-2322 2017/08 [Refereed]
   

  Knock-in mice lacking PKN1 kinase activity were generated by introducing a T778A point mutation in the catalytic domain. PKN1[T778A] mutant mice developed to adulthood without apparent external abnormalities, but exhibited lower T and B lymphocyte counts in the peripheral blood than those of wild-type (WT) mice. T and B cell development proceeded in an apparently normal fashion in bone marrow and thymus of PKN1[T778A] mice, however, the number of T and B cell counts were significantly higher in the lymph nodes and spleen of mutant mice in those of WT mice. After transfusion into WT recipients, EGFP-labelled PKN1[T778A] donor lymphocytes were significantly less abundant in the peripheral circulation and more abundant in the spleen and lymph nodes of recipient mice compared with EGFP-labelled WT donor lymphocytes, likely reflecting lymphocyte sequestration in the spleen and lymph nodes in a cell-autonomous fashion. PKN1[T778A] lymphocytes showed significantly lower chemotaxis towards chemokines and sphingosine 1-phosphate (S1P) than WT cells in vitro. The biggest migration defect was observed in response to S1P, which is essential for lymphocyte egress from secondary lymphoid organs. These results reveal a novel role of PKN1 in lymphocyte migration and localization.
• CCR4 is critically involved in effective antitumor immunity in mice bearing intradermal B16 melanoma.

  Kazuhiko Matsuo; Tatsuki Itoh; Atsushi Koyama; Reira Imamura; Shiori Kawai; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama

  Cancer letters 378 (1) 16 - 22 0304-3835 2016/08 [Refereed]
   

  CCR4 is a major chemokine receptor expressed by Treg cells and Th17 cells. While Treg cells are known to suppress antitumor immunity, Th17 cells have recently been shown to enhance the induction of antitumor cytotoxic T lymphocytes. Here, CCR4-deficient mice displayed enhanced tumor growth upon intradermal inoculation of B16-F10 melanoma cells. In CCR4-deficient mice, while IFN-γ+CD8+ effector T cells were decreased in tumor sites, IFN-γ+CD8+ T cells and Th17 cells were decreased in regional lymph nodes. In wild-type mice, CD4+IL-17A+ cells, which were identified as CCR4+CD44+ memory Th17, were found to be clustered around dendritic cells expressing MDC/CCL22, a ligand for CCR4, in regional lymph nodes. Compound 22, a CCR4 antagonist, also enhanced tumor growth and decreased Th17 cells in regional lymph nodes in tumor-bearing mice treated with Dacarbazine. In contrast, CCR6 deficiency did not affect the tumor growth and the numbers of Th17 cells in regional lymph nodes. These findings indicate that CCR4 is critically involved in regional lymph node DC-Th17 cell interactions that are necessary for Th17 cell-mediated induction of antitumor CD8+ effector T cells in mice bearing B16 melanoma.
• Neolignans from the Arils of Myristica fragrans as Potent Antagonists of CC Chemokine Receptor 3

  Toshio Morikawa; Ikuko Hachiman; Kazuhiko Matsuo; Eriko Nishida; Kiyofumi Ninomiya; Takao Hayakawa; Osamu Yoshie; Osamu Muraoka; Takashi Nakayama

  JOURNAL OF NATURAL PRODUCTS AMER CHEMICAL SOC 79 (8) 2005 - 2013 0163-3864 2016/08 [Refereed]
   

  CC chemokine receptor 3 (CCR3) is expressed selectively in eosinophils, basophils, and some Th2 cells and plays a major role in allergic diseases. A methanol extract from the arils of Myristica fragrans inhibited CC chemokine ligand 11-induced chemotaxis in CCR3-expressing L1.2 cells at 100 mu g/mL. From this extract, eight new neolignans, maceneolignans A-H (1-8), were isolated, and their stereostructures were elucidated from their spectroscopic values and chemical properties. Of those constituents, compounds 1, 4, 6, and 8 and (+)-erythro-(7S,8R)-Delta(8)'-7-hydroxy-3,4-methylenedioxy-3,5'-dimethoxy-8-O-4'-neolignan (11), (-)- (8R)-Delta(8,)-3,4-methylene dioxy-3',5-dimethoxy-8-O-4'-neolignan (17), (+)-licarin A (20), nectandrin B (25), verrucosin (26), and myristicin (27) inhibited CCR3-mediated chemotaxis at, a concentration of 1 mu M. Among them, 1 (EC50 1.6 mu M), 6 (1.5 mu M), and 8 (1.4 mu M) showed relatively strong activities, which were comparable to that of a synthetic CCR3 selective antagonist, SB328437 (0.78 mu M).
• Analysis of Skin Permeability and Toxicological Properties of Amorphous Silica Particles

  Kazuhiko Matsuo; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 39 (7) 1201 - 1205 0918-6158 2016/07 [Refereed]
   

  Nanomaterials (NMs) are defined as those which have nanostructured components less than 100 nm in diameter. They are widely used in various fields such as medicine, cosmetics, and the food industry. However, the toxicological effects of NMs are less well understood than their applications. In particular, the skin is exposed to the environment at all times, so is easily influenced by NMs. In this study, we investigated the skin permeability and toxicological properties of well-dispersed amorphous silica particles with diameters ranging from 70 to 1000 nm, to aid in the safe application of NMs. Amorphous silica particles of 70 nm in size (nSP70) penetrated the living epidermis, following pretreatment with acetone/diethyl ether to improve skin permeation. The application of unmodified nSP70, carboxyl group-modified nSP70, or amino group-modified nSP70 for long durations caused little skin irritation at the application site. Under the present experimental conditions, few adverse systemic effects were evident from blood tests and histopathologic examination. These results suggest that decreasing particle size increases the NMs skin permeability, but remarkably little corresponding skin irritation is observed.
• Vaccination with Antigen Combined with alpha beta-ATP as a Vaccine Adjuvant Enhances Antigen-Specific Antibody Production via Dendritic Cell Activation

  Kazuhiko Matsuo; Satoshi Nishiuma; Yuta Hasegawa; Fumika Kawabata; Kosuke Kitahata; Takashi Nakayama

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 39 (6) 1073 - 1076 0918-6158 2016/06 [Refereed]
   

  Adjuvants are required to enhance antigen-specific immune responses by vaccines. Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X and P2Y receptors and triggers the activation of dendritic cells (DCs). Here we investigated the in vivo adjuvant efficacy of alpha,beta-methylene-ATP (alpha beta-ATP), a non-hydrolysable form of ATP. We found that intradermal injection of ovalbumin (OVA), as a model antigen, combined with alpha beta-ATP, as the adjuvant, enhanced OVA-specific immune responses more than OVA alone. Additionally, DCs in the skin of mice injected with OVA and alpha beta-ATP had increased expression of major histocompatibility complex class II and co-stimulator molecules, CD40, CD80, and CD86, suggesting that alpha beta-ATP activated DC. These findings indicate that alpha beta-ATP functions as a potent vaccine adjuvant.
• Efficient Use of a Crude Drug/Herb Library Reveals Ephedra Herb As a Specific Antagonist for TH2-Specific Chemokine Receptors CCR3, CCR4, and CCR8.

  Kazuhiko Matsuo; Keiichi Koizumi; Mitsugu Fujita; Toshio Morikawa; Michiko Jo; Naotoshi Shibahara; Ikuo Saiki; Osamu Yoshie; Takashi Nakayama

  Frontiers in cell and developmental biology 4 54 - 54 2016 [Refereed]
   

  Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. Taken together, our data suggest that these crude drugs/herbs might be useful sources to develop new drugs targeting TH2-mediated allergic diseases.
• Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch

  Sachiko Hirobe; Hiroaki Azukizawa; Takaaki Hanafusa; Kazuhiko Matsuo; Ying-Shu Quan; Fumio Kamiyama; Ichiro Katayama; Naoki Okada; Shinsaku Nakagawa

  BIOMATERIALS ELSEVIER SCI LTD 57 50 - 58 0142-9612 2015/07 [Refereed]
   

  Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 mu g each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 mu g of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems. (C) 2015 Elsevier Ltd. All rights reserved.
• Erratum: A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens (Journal of Controlled Release (2012) 161 (10-17))

  Kazuhiko Matsuo; Yayoi Yokota; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  Journal of Controlled Release Elsevier 184 (1) 9  1873-4995 2014/06 [Refereed]
  
• Necrobiosis lipoidica with infiltration of Th17 cells into vascular lesions

  Maiko Kato; Naoki Oiso; Tatsuki Itoh; Masako Sato; Kazuhiko Matsuo; Takashi Nakayama; Takao Satou; Akira Kawada

  JOURNAL OF DERMATOLOGY WILEY-BLACKWELL 41 (5) 459 - 461 0385-2407 2014/05 [Refereed]
  
• Vaccine efficacy of transcutaneous immunization with amyloid beta using a dissolving microneedle array in a mouse model of Alzheimer's disease

  Kazuhiko Matsuo; Hideaki Okamoto; Yasuaki Kawai; Ying-Shu Quan; Fumio Kamiyama; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa

  JOURNAL OF NEUROIMMUNOLOGY ELSEVIER SCIENCE BV 266 (1-2) 1 - 11 0165-5728 2014/01 [Refereed]
   

  Vaccine therapy for Alzheimer's disease (AD) based on the amyloid cascade hypothesis has recently attracted attention for treating AD. Injectable immunization using amyloid r3 peptide (A beta) comprising 1-42 amino-acid residues (A beta 1-42) as antigens showed therapeutic efficacy in mice; however, the clinical trial of this injected A beta 1-42 vaccine was stopped due to the incidence of meningoencephalitis caused by excess activation of Th1 cells infiltrating the brain as a serious adverse reaction. Because recent studies have suggested that transcutaneous immunization (TCI) is likely to elicit Th2-dominant immune responses, TCI is expected to be effective in treating AD without inducing adverse reactions. Previously reported TCI procedures employed complicated and impractical vaccination procedures; therefore, a simple, easy-to-use, and novel TCI approach needs to be established. In this study, we investigated the vaccine efficacy of an A beta 1-42-containing TCI using our novel dissolving microneedle array (MicroHyala; MH) against AD. MH-based TCI induced anti-A beta 1-42 immune responses by simple and low-invasive application of A beta 1-42-containing MH to the skin. Unfortunately, this TCI system resulted in little significant improvement in cognitive function and Th2-dominant immune responses, suggesting the need for further modification. (c) 2013 Elsevier B.V. All rights reserved.
• Development and Clinical Study of a Self-Dissolving Microneedle Patch for Transcutaneous Immunization Device

  Sachiko Hirobe; Hiroaki Azukizawa; Kazuhiko Matsuo; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Hiroshi Suzuki; Ichiro Katayama; Naoki Okada; Shinsaku Nakagawa

  PHARMACEUTICAL RESEARCH SPRINGER/PLENUM PUBLISHERS 30 (10) 2664 - 2674 0724-8741 2013/10 [Refereed]
   

  We previously reported the safety and efficacy in animal experiments of transcutaneous immunization (TCI) using a self-dissolving microneedle patch (MicroHyala; MH) made of hyaluronic acid and collagen. However, this MH was an unsuitable TCI device for the human skin, as collagen is suspected to induce inflammation. In this study, we developed an improved collagen-free MH (new-MH) and conducted clinical study to evaluate the fundamental properties and safety in human.Microneedle dissolution, skin irritation, and antigen-specific antibody production about new-MH were measured in mice and/or rats. On the basis of the results, the clinical study was conducted in healthy volunteers to evaluate local and systemic adverse events caused by new-MH application.We confirmed that the microneedles of new-MH, as well as those on our old-MH that contained collagen, could easily pierce stratum corneum without severe skin irritation, and that TCI using new-MH efficiently increased antibody titer with comparable to TCI using old-MH. Application of new-MH caused no severe adverse reactions in 20 healthy volunteers enrolled in a clinical study.These results verified that new-MH is a safe TCI device in human, and greatly encouraged us to advance PI/PII clinical studies of antigen-loaded new-MH.
• Neuroprotective effect of (-)-epigallocatechin-3-gallate in rats when administered pre- or post-traumatic brain injury

  Tatsuki Itoh; Masaki Tabuchi; Nobuyuki Mizuguchi; Motohiro Imano; Masahiro Tsubaki; Shozo Nishida; Shigeo Hashimoto; Kazuhiko Matsuo; Takashi Nakayama; Akihiko Ito; Hiroshi Munakata; Takao Satou

  JOURNAL OF NEURAL TRANSMISSION SPRINGER WIEN 120 (5) 767 - 783 0300-9564 2013/05 [Refereed]
   

  Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2'-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment after TBI was only observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.
• Frontiers of transcutaneous vaccination systems: Novel technologies and devices for vaccine delivery

  Kazuhiko Matsuo; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa

  Vaccine 31 (19) 2403 - 2415 0264-410X 2013/05 [Refereed]
   

  Transcutaneous immunization (TCI) systems that use the skin's immune function are promising needle-free, easy-to-use, and low-invasive vaccination alternative to conventional, injectable vaccination methods. To develop effective TCI systems, it is essential to establish fundamental techniques and technologies that deliver antigenic proteins to antigen-presenting cells in the epidermis and dermis while overcoming the barrier function of the stratum corneum. In this review, we provide an outline of recent trends in the development of techniques for the delivery of antigenic proteins and of the technologies used to enhance TCI systems. We also introduce basic and clinical research involving our TCI systems that incorporate several original devices. © 2013 Elsevier Ltd.
• 臨床研究におけるインフルエンザ経皮ワクチン製剤の免疫誘導特性に関する解析

  廣部 祥子; 小豆澤 宏明; 花房 崇明; 松尾 一彦; 権 英淑; 神山 文男; 片山 一朗; 岡田 直貴; 中川 晋作

  日本薬剤学会年会講演要旨集 (公社)日本薬剤学会 28年会 208 - 208 2013/04
• Analysis of transcutaneous antigenic protein delivery by a hydrogel patch formulation

  Kazuhiko Matsuo; Yumiko Ishii; Yasuaki Kawai; Yuki Saiba; Ying-Shu Quan; Fumio Kamiyama; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa

  Journal of Pharmaceutical Sciences John Wiley and Sons Inc. 102 (6) 1936 - 1947 1520-6017 2013 [Refereed]
   

  We have developed a hydrogel patch, which could promote antigen penetration through stratum corneum (SC), and have demonstrated its safety and efficacy in animals and humans. For the availability improvement of our system, it is important to develop a device, which enhances antigen penetration through SC more efficiently. In this study, we have tried to collect the basic information involved in transcutaneous antigen delivery by investigating the immune event induced by our system and examining the effect of physical property of antigens or patch component on antigen penetration. A hydrogel patch delivered antigens through SC into skin, and some of Langerhans cells captured antigens, activated, and migrated to regional lymph nodes. We also showed that protein distribution into SC was regulated by various complexly-intertwined factors of proteins but not one particular parameter. Additionally, glycerin as the patch component contributed to the formation of SC hydration by patch application, which might be one of the factors of acceleration of protein penetration. On the basis of the present information, we are planning to modify the patch composition and establish the antigen modification technology for improvement in the efficacy of transcutaneous immunization. © 2013 Wiley Periodicals, Inc.
• A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens

  Kazuhiko Matsuo; Yayoi Yokota; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV 161 (1) 10 - 17 0168-3659 2012/07 [Refereed]
   

  Transcutaneous immunization (TCI) is a promising needle-free, easy-to-use, and low-invasive vaccination method. The hydrogel patch-based TCI system induced immune responses against soluble antigens (Ags) like toxoids, but could not induce immune responses against particulate Ags. Here, as an effective TCI system against every form of Ag, we developed a dissolving microneedle array of three lengths (200, 300, or 800 mu m) made of hyaluronate as a novel TCI device. Unlike conventional microneedles, the microneedles of our dissolving microneedle arrays dissolved in the skin after insertion. Each dissolving microneedle array effectively delivered both soluble and particulate Ags under the stratum corneum. TCI using these dissolving microneedle arrays induced effective immune responses in rats regardless of the Ag form that were comparable to conventional vaccination using subcutaneous immunization. In addition, application of these dissolving microneedle arrays caused only slight skin irritation. These findings suggest that our TCI system can simply, safely, and effectively improve protective immune responses for every vaccine Ag. (C) 2012 Elsevier B.V. All rights reserved.
• インフルエンザHA抗原装填マイクロニードルパッチ製剤のヒトにおける安全性・有効性の検証

  廣部 祥子; 小豆澤 宏明; 花房 崇明; 仁木 一順; 松尾 一彦; 権 英淑; 神山 文男; 片山 一朗; 向 洋平; 岡田 直貴; 中川 晋作

  日本DDS学会学術集会プログラム予稿集 日本DDS学会 28回 128 - 128 2012/06
• Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza

  Kazuhiko Matsuo; Sachiko Hirobe; Yayoi Yokota; Yurika Ayabe; Masashi Seto; Ying-Shu Quan; Fumio Kamiyama; Takahiro Tougan; Toshihiro Horii; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV 160 (3) 495 - 501 0168-3659 2012/06 [Refereed]
   

  Transcutaneous immunization (TCI) is an attractive alternative vaccination route compared to the commonly used injection systems. We previously developed a dissolving microneedle array for use as a TCI device, and reported that TCI with the dissolving microneedle array induced an immune response against model antigens. In the present study, we investigated the vaccination efficacy against tetanus and diphtheria, malaria, and influenza using this vaccination system. Our TCI system induced substantial increases in toxoid-specific IgG levels and toxin-neutralizing antibody titer and induced the production of anti-SE36 IgG, which could bind to malaria parasite. On influenza HA vaccination, robust antibody production was elicited in mice that provided complete protection against a subsequent influenza virus challenge. These findings demonstrate that TCI using a dissolving microneedle array can elicit large immune responses against infectious diseases. Based on these results, we are now preparing translational research for human clinical trials. (C) 2012 Elsevier B.V. All rights reserved.
• Clinical study of transcutaneous vaccination using a hydrogel patch for tetanus and diphtheria

  Sachiko Hirobe; Kazuhiko Matsuo; Ying-Shu Quan; Fumio Kamiyama; Hironori Morito; Hideo Asada; Yusuke Takaya; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  VACCINE ELSEVIER SCI LTD 30 (10) 1847 - 1854 0264-410X 2012/02 [Refereed]
   

  Transcutaneous immunization (TCI) is a non-invasive and easy-to-use vaccination method. We demonstrated the efficacy and safety of a transcutaneous vaccine formulation using a hydrogel patch in animal experiments. In the present study, we performed a clinical study to apply our TCI formulation for vaccination against tetanus and diphtheria in human. The TCI device was a hydrogel patch (antigen-free) applied to the left brachial medial skin of 22 healthy volunteers for 48 h. Next, the hydrogel patch, containing 2 mg tetanus toxoid (TT) and 2 mg diphtheria toxoid (DT) as the TCI formulation, was applied to 27 healthy volunteers for 24 h and some volunteers were vaccinated again by TCI formulation. For safety assessment, the patch application site was observed to assess local adverse events, and systemic adverse events were determined by a blood test. The antigen-free hydrogel patch and TCI formulation containing TT and DT did not induce local or systemic severe adverse events. For vaccine efficacy estimation, toxoid-specific serum antibody titers were determined by ELISA and the toxin-neutralizing activity of the induced antibody was evaluated in a passive-challenge experiment. The anti-TT IgG titer and the anti-DT IgG titer increased, and a significant effect was detected by paired t-test. The antibody titers were maintained at higher level than that before vaccination for at least 1 year. Moreover, toxoid-specific antibodies were produced by the second vaccination in some subjects. Antibodies induced by application of the TCI formulation neutralized the toxin and prevented toxic death in mice. In addition, changes in the skin condition due to application of the TCI formulation were observed under in vivo confocal Raman spectroscopy. The amount of water and patch components in the stratum corneum increased after application of the TCI formulation, suggesting that the change in the skin condition was related to antigen penetration. These data indicate that this easy-to-use TCI system induces an immune response without severe adverse reactions in humans. This easy-to-use and safe TCI formulation enables mass treatment in an outbreak setting and increased vaccination rates in developing countries, and will greatly contribute to worldwide countermeasures against infectious diseases. (C) 2012 Elsevier Ltd. All rights reserved.
• Induction of Endoplasmic Reticulum-Endosome Fusion for Antigen Cross-Presentation Induced by Poly (gamma-Glutamic Acid) Nanoparticles

  Yohei Mukai; Tomoyo Yoshinaga; Mai Yoshikawa; Kazuhiko Matsuo; Tomoaki Yoshikawa; Keisuke Matsuo; Kazuyuki Niki; Yasuo Yoshioka; Naoki Okada; Shinsaku Nakagawa

  JOURNAL OF IMMUNOLOGY AMER ASSOC IMMUNOLOGISTS 187 (12) 6249 - 6255 0022-1767 2011/12 [Refereed]
   

  We previously reported that poly (gamma-glutamic acid)-based nanoparticles (gamma-PGA NPs) are excellent vaccine carriers for inducing efficient cross-presentation in dendritic cells, thereby producing strong antitumor immunity in vivo. Analyzing the mechanism of cross-presentation induced by gamma-PGA NPs will be useful toward designing novel vaccine carriers. In this study, we show an intracellular mechanism of efficient cross-presentation induced by OVA-loaded gamma-PGA NPs. Cross-presentation induced by gamma-PGA NPs depended on cytoplasmic proteasomes and TAP, similar to the classical MHC class I presentation pathway for endogenous Ags. Intracellular behavior analyzed by confocal laser scanning microscopy revealed that encapsulated OVA and gamma-PGA accumulated in both the endoplasmic reticulum (ER) and endosome compartments within 2 h. At the same time, electron microscopy analysis clearly showed that intracellular gamma-PGA NPs and encapsulated Au NPs were enveloped in endosome-like vesicles, not in the ER. These findings strongly suggest that gamma-PGA NPs enhance ER-endosome fusion for cross-presentation. Moreover, inhibition of ER translocon sec61 significantly decreased the gamma-PGA NP/OVA-mediated cross-presentation efficiency, indicating that sec61 is important for transporting Ags from the fused ER-endosome to the cytoplasm. These findings imply that the ER-endosome complex is key for the efficient cross-presentation of Ags encapsulated in gamma-PGA NPs. The Journal of Immunology, 2011, 187: 6249-6255.
• Compositional Optimization and Safety Assessment of a Hydrogel Patch as a Transcutaneous Immunization Device

  Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Hideo Asada; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 34 (12) 1835 - 1840 0918-6158 2011/12 [Refereed]
   

  The development of a simple, easy-to-use, and non-invasive vaccination system is in high demand. For transcutaneous immunization (TCI), we previously developed a hydrogel patch formulation that accelerates the penetration of an antigen (Ag) through the stratum corneum (SC) and effectively elicits Ag-specific immune responses. The present studies were performed to optimize the composition and assess the safety of the patch formulation. A hydrogel patch with a water content ratio of 5% more effectively induced an immune response compared to patches. with a different composition, suggesting that the moisture content of the hydrogel patch formulation has optimal ratio for SC hydration to promote Ag penetration through the SC. TCI using a hydrogel patch induced few local and systemic adverse reactions. Based on these results, we are now advancing translational research to evaluate the safety and efficacy of our novel TCI system in humans.
• [Development of transcutaneous vaccine formulations for the infectious disease countermeasure].

  Kazuhiko Matsuo; Naoki Okada; Shinsaku Nakagawa

  Nihon rinsho. Japanese journal of clinical medicine 69 (9) 1561 - 6 0047-1852 2011/09 [Refereed]
   

  The recent vigorous transnational migration of people and materials reflecting the development of transportation facilities have increased the global spread of infections. On the basis of this social background, the development of vaccination, which is the only fundamental prophylaxis, is in attention. Even if, however, rapid manufacture of vaccine antigen is actualized, there are several problems that vaccine is not easily spread across the developing country, because conventional vaccination is performed mainly by injection. Our group developed two transcutaneous vaccine devices which delivered antigens to antigen-presenting cells: a hydrogel patch and a dissolving microneedle patch. Our transcutaneous immunization system using these devices receives a high evaluation as novel, easy-to-use, and low-invasive vaccination method against infections from home and abroad.
• Intranasal immunization with poly(γ-glutamic acid) nanoparticles entrapping antigenic proteins can induce potent tumor immunity.

  Matsuo K; Koizumi H; Akashi M; Nakagawa S; Fujita T; Yamamoto A; Okada N

  Journal of controlled release : official journal of the Controlled Release Society 152 (2) 310 - 316 0168-3659 2011/06 [Refereed]
  
• 皮膚内溶解型マイクロニードルの穿刺特性および安全性に関する臨床研究

  廣部 祥子; 松尾 一彦; 権 英淑; 神山 文男; 小豆澤 宏明; 片山 一朗; 鈴木 博; 向 洋平; 岡田 直貴; 中川 晋作

  Drug Delivery System 日本DDS学会 26 (3) 312 - 312 0913-5006 2011/05
• Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application

  Hiromi Nabeshi; Tomoaki Yoshikawa; Keigo Matsuyama; Yasutaro Nakazato; Kazuhiko Matsuo; Akihiro Arimori; Masaaki Isobe; Saeko Tochigi; Sayuri Kondoh; Toshiro Hirai; Takanori Akase; Takuya Yamashita; Kohei Yamashita; Tokuyuki Yoshida; Kazuya Nagano; Yasuhiro Abe; Yasuo Yoshioka; Haruhiko Kamada; Takayoshi Imazawa; Norio Itoh; Shinsaku Nakagawa; Tadanori Mayumi; Shin-ichi Tsunoda; Yasuo Tsutsumi

  BIOMATERIALS ELSEVIER SCI LTD 32 (11) 2713 - 2724 0142-9612 2011/04 [Refereed]
   

  Currently, nanomaterials (NMs) with particle sizes below 100 nm have been successfully employed in various industrial applications in medicine, cosmetics and foods. On the other hand, NMs can also be problematic in terms of eliciting a toxicological effect by their small size. However, biological and/or cellular responses to NMs are often inconsistent and even contradictory. In addition, relationships among NMs physicochemical properties, absorbency, localization and biological responses are not yet well understood. In order to open new frontiers in medical, cosmetics and foods fields by the safer NMs, it is necessary to collect the information of the detailed properties of NMs and then, build the prediction system of NMs safety. The present study was designed to examine the skin penetration, cellular localization, and cytotoxic effects of the well-dispersed amorphous silica particles of diameters ranging from 70 nm to 1000 nm. Our results suggested that the well-dispersed amorphous nanosilica of particle size 70 nm (nSP70) penetrated the skin barrier and caused systemic exposure in mouse, and induced mutagenic activity in vitro. Our information indicated that further studies of relation between physicochemical properties and biological responses are needed for the development and the safer form of NMs. (C) 2011 Elsevier Ltd. All rights reserved.
• Characterization of Transcutaneous Protein Delivery by a Hydrogel Patch in Animal, Human, and Tissue-Engineered Skin Models

  Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 34 (4) 586 - 589 0918-6158 2011/04 [Refereed]
   

  The development of a simple, easy-to-use, and noninvasive vaccination system is in high demand. For transcutaneous immunization (TCI), we previously reported that a hydrogel patch was an effective TCI device that accelerates antigen penetration through the stratum corneum in mouse and rat models. The present study was performed to characterize the transcutaneous protein delivery induced by the hydrogel patch in mouse, guinea pig, LWD pig, human, or tissue-engineered skin models, and to assess the activity of proteins delivered into the skin. The hydrogel patch promoted protein penetration through the stratum corneum in all skin models, indicating that our original hydrogel patch might have practical application for use in humans. In addition, proteins delivered into the skin by the hydrogel patch retained their activity, suggesting that the hydrogel patch is applicable for the delivery of therapies for other diseases as well. On the basis of these results, translational research in human is now in progress.
• 生分解性マイクロニードルの安全性評価に関する臨床研究

  廣部 祥子; 松尾 一彦; 平石 恭大; Zhai You; 権 英淑; 神山 文男; 小豆澤 宏明; 片山 一朗; 鈴木 博; 向 洋平; 岡田 直貴; 中川 晋作

  日本薬学会年会要旨集 (公社)日本薬学会 131年会 (4) 188 - 188 0918-9823 2011/03
• Transcutaneous vaccination using a hydrogel patch induces effective immune responses to tetanus and diphtheria toxoid in hairless rat

  Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Yasuo Yoshioka; Naoki Okada; Shinsaku Nakagawa

  JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV 149 (1) 15 - 20 0168-3659 2011/01 [Refereed]
   

  Transcutaneous immunization (TCI) targeting the Langerhans cells (LCs) of the epidermal layer is a promising needle-free, easy-to-use, and non-invasive vaccination method. We developed a hydrogel patch formulation to promote the penetration of antigenic proteins into the stratum corneum. Here, we investigated the characteristics of the immune responses induced by this vaccination method and the vaccine efficacy of TCI using a hydrogel patch containing tetanus and diphtheria toxoids. Our TCI system induced toxoid-specific IgG production in an antigen dose-, patch area-, and application period-dependent manner. Moreover, IgG subclass analysis indicated that our TCI predominantly elicited a Th2-type immune response rather than a Th1-type immune response. Importantly, our TCI system induced antigen-specific immune memory based on the booster effect and showed potent efficacy, comparable to that of subcutaneous immunization in toxin-challenge experiments. On the basis of these results, we are now performing translational research to apply TCI for tetanus and diphtheria. (C) 2010 Elsevier B.V. All rights reserved.
• The Utility of Poly(gamma-glutamic acid) Nanoparticles as Antigen Delivery Carriers in Dendritic Cell-Based Cancer Immunotherapy

  Keisuke Matsuo; Yumiko Ishii; Kazuhiko Matsuo; Tomoyo Yoshinaga; Mitsuru Akashi; Yohei Mukai; Yasuo Yoshioka; Naoki Okada; Shinsaku Nakagawa

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 33 (12) 2003 - 2007 0918-6158 2010/12 [Refereed]
   

  Cytotoxic T-lymphocytes (CTLs) specific for tumor-associated antigens (TAAs) act in the immune surveillance system as major effector cells to eliminate malignant cells Immunization with TAA-loaded dendritic cells (DCs) has great potential for treating cancer, because DCs are potent antigen-presenting cells capable of inducing antigen-specific CTLs by the primary activation of naive T-lymphocytes The establishment of a non-cyto-toxic and efficient antigen delivery method is required to Improve the efficacy of DC-based cancer immunotherapy We developed biodegradable poly(gamma-glutamic acid) nanoparticles (gamma-PGA NPs) that can efficiently entrap various proteins as antigen delivery carriers gamma-PGA NPs efficiently delivered entrapped antigenic proteins into DCs without cytotoxicity and presented antigens to DCs via major histocompatibility complex class I and II molecules Immunization with TAA-loaded DCs using gamma-PGA NPs inhibited tumor growth by inducing TAA-specific CTLs These findings indicate that gamma-PGA NPs can function as useful antigen delivery carriers in DC-based cancer Immunotherapy
• 新規経皮ワクチンデバイスを用いた「貼るワクチン」の開発

  松尾一彦; 権 英淑; 岡田直貴; 中川晋作

  BIO Clinica 25 (5) 39 - 43 2010/05 [Invited]
  
• 「貼るワクチン」の開発 生分解性マイクロニードルを用いたマラリアワクチンの開発

  綾部 有里香; 松尾 一彦; 権 英淑; 神山 文男; 堀井 俊宏; 向 洋平; 吉岡 靖雄; 岡田 直貴; 中川 晋作

  日本薬学会年会要旨集 (公社)日本薬学会 130年会 (4) 163 - 163 0918-9823 2010/03
• Development of transcutaneous vaccine formulations based on DDS technology

  Matsuo Kazuhiko; Okada Naoki; Nakagawa Shinsaku

  Drug Delivery System THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM 25 (1) 8 - 14 0913-5006 2010 

  Transcutaneous immunization (TCI) system utilizing skin immune function is a promising needle-free, easy-to-use, and non-invasive vaccination method instead of conventional injectable vaccination method. For effective TCI system, it is essential to establish the fundamental techniques that antigenic proteins were delivered to antigen-presenting cells in the epidermal layer.
  In this review, we give outline of recent research trend about antigenic protein delivery techniques for TCI and introduce our basic and preclinical research about TCI using our original hydrogel patch formulation containing antigenic proteins.
• A transcutaneous vaccination system using a hydrogel patch for viral and bacterial infection

  Yumiko Ishii; Tomoko Nakae; Fumiko Sakamoto; Kazuhiko Matsuo; Keisuke Matsuo; Ying-Shu Quan; Fumio Kamiyama; Takuya Fujita; Akira Yamamoto; Shinsaku Nakagawa; Naoki Okada

  JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV 131 (2) 113 - 120 0168-3659 2008/10 [Refereed]
   

  One of the most important anthropic missions is preventing the global spread of infectious diseases. Vaccination is the only available preventive treatment for infectious diseases, but the availability of vaccines in developing countries is not adequate. We report a simple, easy-to-use, noninvasive hydrogel patch transcutaneous vaccination system. Antigen (Ag)-specific IgG production was induced by applying an Ag-immersed patch to non-pretreated mouse auricle or hairless rat back skin. Immunofluorescence histochemical analysis revealed that Langerhans cells resident in the epidermal layer captured the antigenic proteins delivered by the hydrogel patch, which promoted the penetration of antigenic proteins through the stratum corneum, and that Ag-capturing Langerhans cells migrated into draining lymph nodes. Humoral immunity elicited by our transcutaneous vaccination system demonstrated neutralizing activity in both adenoviral infection and passive-challenge tetanus toxin experiments. The use of this hydrogel patch transcutaneous vaccination system will facilitate the global distribution of effective and convenient vaccines. (C) 2008 Elsevier B.V. All rights reserved.
• Nanoparticles built by self-assembly of amphiphilic gamma-PGA can deliver antigens to antigen-presenting cells with high efficiency: A new tumor-vaccine carrier for eliciting effector T cells

  Tomoaki Yoshikawa; Naoki Okada; Atsushi Oda; Keisuke Matsuo; Kazuhiko Matsuo; Hiroyuki Kayamuro; Yumiko Ishii; Tomoyo Yoshinaga; Takami Akagi; Mitsuru Akashi; Shinsaku Nakagawa

  VACCINE ELSEVIER SCI LTD 26 (10) 1303 - 1313 0264-410X 2008/03 [Refereed]
   

  Nanotechnology is a fundamental technology for designing and generating innovative carriers for biomacromolecular drugs. Biodegradable poly(- -glutamic acid)-based nanoparticles (gamma-PGA NPs) are excellent vaccine carriers capable of delivering antigenic proteins to antigen -presenting cells (APCs) and eliciting potent immune responses based on antigen -specific cytotoxic T lymphocytes. In mice, subcutaneous immunization with gamma-PGA NPs entrapping ovalbumin (OVA) more effectively inhibited the growth of OVA-transfected tumors than immunization with OVA emulsified using Freund's complete adjuvant. In addition, gamma-PGA NPs did not induce histopathotogic changes after subcutaneous injection or acute toxicity through intravenous injection. Importantly, gamma-PGA NPs efficiently delivered entrapped antigenic (C) 2008 Elsevier Ltd. All rights reserved.
• Development of amphiphilic gamma-PGA-nanoparticle based tumor vaccine: Potential of the nanoparticulate cytosolic protein delivery carrier

  Tomoaki Yoshikawa; Naoki Okada; Atsushi Oda; Kazuhiko Matsuo; Keisuke Matsuo; Yohei Mukai; Yasuo Yoshioka; Takami Akagi; Mitsuru Akashi; Shinsaku Nakagawa

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 366 (2) 408 - 413 0006-291X 2008/02 [Refereed]
   

  Nanoscopic therapeutic systems that incorporate biomacromolecules, such as protein and peptides, are emerging as the next generation of nanomedicine aimed at improving the therapeutic efficacy of biomacromolecular drugs. In this study, we report that poly(gamma-glutamic acid)-based nanoparticles (gamma-PGA NPs) are excellent protein delivery carriers for tumor vaccines that delivered antigenic proteins to antigen-presenting cells and elicited potent immune responses. Importantly, gamma-PGA NPs efficiently delivered entrapped antigenic proteins through cytosolic translocation from the endosomes, which is a key process of gamma-PGA NP-mediated anti-tumor immune responses. Our findings suggest that the gamma-PGA NP system is suitable for the intracellular delivery of protein-based drugs as well as tumor vaccines. (C) 2007 Published by Elsevier Inc.

Books etc

• 応用が拡がるDDS ― 人体環境から農業・家電まで ―

  松尾一彦; 岡田直貴; 中川晋作 (Joint work)エヌ・ティー・エス 2013/07
• Bio-Nanotechnology: A Revolution in Food, Biomedical and Health Sciences

  Kazuhiko Matsuo; Naoki Okada; Shinsaku Nakagawa (Joint work)Wiley-Blackwell 2013/01
• ドラッグデリバリーシステムの新展開II ― 核酸医薬・抗体医薬・ワクチン医療を支えるDDS技術

  松尾一彦; 岡田直貴; 中川晋作 (Joint work)シーエムシー出版 2012/03
• 次世代バイオ医薬品の製剤設計と開発戦略

  松尾一彦; 岡田直貴; 中川晋作 (Joint work)シーエムシー出版 2011/11
• 次世代経皮吸収型製剤の開発と応用

  松尾一彦; 岡田直貴; 中川晋作 (Joint work)シーエムシー出版 2011/07
• 次世代ワクチンの産業応用技術

  松尾一彦; 岡田直貴; 中川晋作 (Joint work)シーエムシー出版 2010/09

MISC

• CCR4 antagonist ameliorated atopi dermatitis by inhibiting infiltration and expansion of CCR4-expressing Th2 cells and Th17 cells in mice

  山下絢香; 松尾一彦; 須佐美陽子; 早坂晴子; 原雄大; 中山隆志  日本薬学会年会要旨集(Web)  143rd-  2023
• Chemokine CCL28-mediated antitumor immunity against a murine melanoma

  西田晃尚; 山本真也; 松尾一彦; 早坂晴子; 海堀祐一郎; 長久保大輔; 原雄大; 義江修; 義江修; 中山隆志  日本薬学会年会要旨集(Web)  143rd-  2023
• Neolignan from the fruit of Alpinia galanga as antagonists of CC chemokine receptor-3

  坂本裕介; 萬瀬貴昭; 楡光世; 綿原光司; 原雄大; 松尾一彦; 中山隆志; 森川敏生; 森川敏生  日本農芸化学会大会講演要旨集(Web)  2022-  2022
• 紅豆こう(Alpinia galanga,果実)ケモカイン受容体CCR3選択的アンタゴニスト作用を指標とした抗アレルギー作用成分の探索

  森川敏生; 森川敏生; 萬瀬貴昭; 坂本祐介; 綿原光司; 原雄大; 松尾一彦; 中山隆志  日本生薬学会年会講演要旨集  67th-  2021
• 細胞遊走

  松尾 一彦; 中山 隆志  ファルマシア  56-  (4)  335_2  -335_2  2020
• ホーミング

  松尾 一彦; 中山 隆志  ファルマシア  56-  (4)  335_3  -335_3  2020
• Chemokine receptors and cell migration

  松尾一彦; 中山隆志  日本血栓止血学会誌  30-  (4)  610‐618(J‐STAGE)  -618  2019
• Search for chemokine receptor CCR3 selective antagonist as anti-allergic principles from mace, the arils of Myristica fragrans

  Morikawa Toshio; Matsuo Kazuhiko; Hachiman Ikuko; Ninomiya Kiyofumi; Muraoka Osamu; Nakayama Takashi  Symposium on the Chemistry of Natural Products, symposium papers  56-  (0)  2018/07
• メース(Myristica fragrans,仮種皮)のケモカイン受容体CCR3アンタゴニスト様作用を指標とした抗アレルギー作用成分の探索

  森川敏生; 森川敏生; 八幡郁子; 松尾一彦; 西田枝里子; 二宮清文; 二宮清文; 義江修; 村岡修; 村岡修; 中山隆志  食品薬学シンポジウム講演要旨集  7th-  134‐136  2017/10
• ケモカイン受容体を標的とした天然由来シーズの探索研究(2):ロウバイカ(Chimonanthus praecox花蕾部)のCCR6およびCCR7アンタゴニスト活性成分

  森川敏生; 松尾一彦; 奥川修平; 奥川修平; 北川仁一朗; 北川仁一朗; 二宮清文; 中西勇介; 村岡修; 村岡修; 中山隆志; 中山隆志  日本生薬学会年会講演要旨集  63rd-  146  2016/08
• 和漢薬ライブラリーを利用したケモカイン受容体CCR3及びCCR4のアンタゴニスト成分の探索

  北田 卓也; 松尾 一彦; 小泉 桂一; 義江 修; 中山 隆志  日本薬学会年会要旨集  135年会-  (3)  167  -167  2015/03
• メースの機能性成分(4);ケモカイン受容体CCR3選択的アゴニスト作用成分の探索

  森川敏生; 八幡郁子; 松尾一彦; 二宮清文; 村岡修; 中山隆志  日本生薬学会年会講演要旨集  61st-  118  2014/08
• Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza (vol 160, pg 495, 2012)

  Kazuhiko Matsuo; Sachiko Hirobe; Yayoi Yokota; Yurika Ayabe; Masashi Seto; Ying-Shu Quan; Fumio Kamiyama; Takahiro Tougan; Toshihiro Horii; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa  JOURNAL OF CONTROLLED RELEASE  184-  18  -19  2014/06
• A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens (vol 161, pg 10, 2012)

  Kazuhiko Matsuo; Yayoi Yokota; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa  JOURNAL OF CONTROLLED RELEASE  184-  9  -9  2014/06
• 小児感染症の予防2014 I.ワクチンによる小児感染症の予防 12.次世代ワクチンの開発 2)「貼るワクチン」による感染症予防の試み

  松尾一彦; 岡田直貴; 中川晋作  小児科臨床  67-  (4)  607  -614  2014/04
• Development of vaccine adjuvant targeting the chemokine-chemokine receptor axis

  Kazuhiko Matsuo  Drug Delivery System  29-  (3)  246  -247  2014
• Search for chemokine receptor CCR3 selective antagonist as anti-allergic principles from mace, the arils of Myristica fragrans

  Morikawa Toshio; Matsuo Kazuhiko; Hachiman Ikuko; Ninomiya Kiyofumi; Muraoka Osamu; Nakayama Takashi  Symposium on the Chemistry of Natural Products, symposium papers  56-  (0)  2014
• 和漢薬の科学基盤 共同研究による先駆的統合的解明 標準和漢薬ライブラリーを用いたケモカイン受容体CCR3およびCCR4アンタゴニストの探索 アレルギー疾患を標的として

  中山 隆志; 田中 宏幸; 松尾 一彦; 小泉 桂一; 義江 修  日本薬学会年会要旨集  133年会-  (1)  146  -146  2013/03
• Application of Poly(γ-Glutamic Acid)-Based Nanoparticles as Antigen Delivery Carriers in Cancer Immunotherapy

  Kazuhiko Matsuo; Naoki Okada; Shinsaku Nakagawa  Bio-Nanotechnology: A Revolution in Food, Biomedical and Health Sciences  487  -505  2013/01
• Development of Transcutaneous Vaccination System for Infectious Disease Countermeasure

  Kazuhiko Matsuo  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN  132-  (12)  1443  -1450  2012/12
• 新型インフルエンザパンデミックに即時対応できる経皮ワクチンシステムの開発

  仁木一順; 松尾一彦; 廣部祥子; 権英淑; 神山文男; 向洋平; 岡田直貴; 中川晋作  日本薬学会年会要旨集  132年会-  (4)  207  -207  2012/03
• 経皮ワクチン製剤のヒトにおける安全性および有効性の評価

  廣部祥子; 松尾一彦; 岡田直貴; 中川晋作  日本免疫学会総会・学術集会記録  40-  127  -127  2011/11
• アルツハイマー病モデルマウスにおけるアミロイドβ装填マイクロニードル製剤の経皮ワクチン効果

  岡本英揚; 松尾一彦; 岡田直貴; 中川晋作  日本免疫学会総会・学術集会記録  40-  127  -127  2011/11
• 皮膚内溶解型マイクロニードルを応用した経皮免疫製剤の感染防御効果

  松尾一彦; 廣部祥子; 岡田直貴; 中川晋作  日本免疫学会総会・学術集会記録  40-  127  -127  2011/11
• The development of microneedle-based transcutaneous immunization system

  松尾 一彦; 岡田 直貴; 中川 晋作  綜合臨床  60-  (11)  2211  -2214  2011/11
• 皮膚内溶解型マイクロニードルを用いたアトピー性皮膚炎治療法の可能性

  仁木一順; 廣部祥子; 松尾一彦; 権英淑; 神山文男; 向洋平; 岡田直貴; 中川晋作  Aesthetic Dermatol  21-  (2)  180  -180  2011/09
• ワクチン II.ワクチン基礎研究の最新動向と展望 感染症予防対策に資する経皮免疫製剤(貼るワクチン)の開発

  松尾一彦; 岡田直貴; 中川晋作  日本臨床  69-  (9)  1561  -1566  2011/09
• 生分解性マイクロニードルを応用したアトピー性皮膚炎治療法の可能性

  仁木一順; 松尾一彦; 廣部祥子; 権英淑; 神山文男; 向洋平; 岡田直貴; 中川晋作  日本薬学会年会要旨集  131年会-  (4)  189  -189  2011/03
• 臨床研究用生分解性マイクロニードルの作製と機能評価

  ZHAI You; 松尾一彦; 権英淑; 神山文男; 向洋平; 岡田直貴; 中川晋作  日本薬学会年会要旨集  131年会-  (4)  189  -189  2011/03
• 生分解性マイクロニードルを用いたインフルエンザ経皮ワクチンの有効性

  松尾一彦; 横田やよい; 権英淑; 神山文男; 鎌田良男; 向洋平; 岡田直貴; 中川晋作  日本薬学会年会要旨集  131年会-  (4)  189  -189  2011/03
• ワクチンに関する最新の話題―新しいワクチン時代の幕開け 新しいワクチン開発 感染症予防対策に向けた新規経皮ワクチン製剤の開発

  松尾一彦; 岡田直貴; 中川晋作  臨床と微生物  37-  (3)  207  -212  2010/05
• ワクチンの新たな展開 6 新規経皮ワクチンデバイスを用いた「貼るワクチン」の開発

  松尾一彦; QUAN Ying‐Shu; 岡田直貴; 中川晋作  Bio Clinica  25-  (5)  401  -405  2010/05
• 破傷風・ジフテリア経皮ワクチン製剤のヒトにおける安全性・有効性の検証

  廣部祥子; 松尾一彦; 権英淑; 神山文男; 浅田秀夫; 高矢雄介; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  311  -311  2010/05
• 親水性ゲルパッチによる抗原の角質層透過促進機構に関する検討

  岡本英揚; 松尾一彦; 川合泰明; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  311  -311  2010/05
• 生分解性マイクロニードルの経皮ワクチンデバイスとしての特性

  横田やよい; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  311  -311  2010/05
• 多種多様な抗原に適用できる新規経皮ワクチン製剤の開発

  齋塲雄貴; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  312  -312  2010/05
• アルツハイマー病に対する治療効果を狙った経皮ワクチン療法の開発

  亀井数正; 松尾一彦; 川合泰明; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  312  -312  2010/05
• マラリア撲滅に向けた新規経皮ワクチン製剤の開発

  松尾一彦; 綾部有里香; 権英叔; 神山文男; 堀井俊宏; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Delivery System  25-  (3)  312  -312  2010/05
• 感染症パンデミックの抑止に貢献する新規経皮ワクチン製剤の開発

  松尾一彦; 岡田直貴; 中川晋作  薬剤学  70-  (Supplement)  68  -68  2010/04
• 感染症対策に資する画期的「貼るワクチン」の開発

  松尾一彦; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (1)  382  -382  2010/03
• 「貼るワクチン」の開発 I~親水性ゲルパッチによる抗原蛋白質の角質層透過に関する検討~

  岡本英揚; 川合泰明; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  162  -162  2010/03
• 「貼るワクチン」の開発 III~生分解性マイクロニードルによる経皮抗原デリバリーに関する検討~

  横田やよい; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  163  -163  2010/03
• 「貼るワクチン」の開発 V~生分解性マイクロニードルを用いた破傷風・ジフテリアワクチンの開発~

  廣部祥子; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  163  -163  2010/03
• 「貼るワクチン」の開発 IV~生分解性マイクロニードルによる可溶性抗原および粒子状抗原に対する免疫誘導~

  瀬戸正志; 松尾一彦; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  163  -163  2010/03
• 「貼るワクチン」の開発 II~親水性ゲルパッチを用いた経皮ワクチンの臨床研究~

  齊塲雄貴; 松尾一彦; 権英淑; 神山文男; 浅田秀夫; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  163  -163  2010/03
• 「貼るワクチン」の開発 VI~生分解性マイクロニードルを用いたマラリアワクチンの開発~

  綾部有里香; 松尾一彦; 権英淑; 神山文男; 堀井俊宏; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  130年会-  (4)  163  -163  2010/03
• 新規香粧品素材として注目されるナノシリカの経皮リスクに関する基礎検討

  松尾一彦; 免山智行; 角田慎一; 堤康央; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本香粧品学会誌  33-  (3)  218  -219  2009/09
• 親水性ゲルパッチを用いた経皮免疫製剤のアジュバント併用時の有効性評価

  齋場雄貴; 松尾一彦; 石井裕美子; 川合泰明; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  Drug Deliv Syst  24-  (3)  322  -322  2009/06
• ナノシリカの皮膚透過性と経皮リスクに関する基礎検討

  松尾一彦; 免山智行; 角田慎一; 堤康央; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  129年会-  (4)  286  -286  2009/03
• 破傷風・ジフテリアに対する経皮免疫製剤の実用化に向けた基礎的検討

  川合泰明; 松尾一彦; 石井裕美子; 齋塲雄貴; 権英淑; 神山文男; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  129年会-  (4)  165  -165  2009/03
• 感染症対策に向けた次世代型ワクチン : 貼るワクチンの開発(セミナー)

  松尾 一彦; 岡田 直貴; 中川 晋作  ファルマシア  45-  (4)  333  -337  2009
• 抗原送達キャリアーとしてγ-PGAナノ粒子を用いた経鼻投与型癌ワクチンの開発(Development of nasal administration-type cancer vaccine using γ-PGA nanoparticle as an antigen delivery carrier)

  松尾 一彦; 松尾 圭祐; 赤木 隆美; 明石 満; 向 洋平; 吉岡 靖雄; 岡田 直貴; 中川 晋作  日本癌学会総会記事  66回-  425  -425  2007/08
• 抗原内包γ‐PGAナノ粒子の経鼻投与による腫瘍免疫誘導

  小泉勇人; 松尾一彦; 坂本史子; 溝内亜希子; 松尾圭祐; 吉川友章; 赤木隆美; 明石満; 中川晋作; 藤田卓也; 山本昌; 岡田直貴  日本薬学会年会要旨集  127年会-  (3)  86  -86  2007/03
• 抗原内包γ‐PGAナノ粒子の免疫誘導機構と安全性に関する検討

  松尾圭祐; 吉川友章; 萱室裕之; 松尾一彦; 赤木隆美; 明石満; 向洋平; 吉岡靖雄; 岡田直貴; 中川晋作  日本薬学会年会要旨集  127年会-  (3)  86  -86  2007/03
• 抗原内包γ‐PGAナノ粒子を用いた癌免疫療法におけるエフェクター細胞機能および安全性の評価

  萱室裕之; 松尾圭祐; 松尾一彦; 吉川友章; 明石満; 岡田直貴; 中川晋作  日本免疫学会総会・学術集会記録  36-  37  -37  2006/11
• 癌免疫療法における抗原送達キャリアーとしてのγ-PGAナノ粒子の有用性

  松尾 一彦; 吉川 友章; 赤木 隆美; 明石 満; 岡田 直貴; 中川 晋作  日本癌学会総会記事  65回-  321  -321  2006/09
• 抗原蛋白質を内包したγ‐PGAナノ粒子の特性評価と抗腫ようワクチンキャリアーへの応用

  吉川友章; 小田淳史; 丹羽貴子; 松尾一彦; 萱室裕之; 堤康央; 赤木隆美; 明石満; 岡田直貴; 中川晋作  日本薬学会年会要旨集  126年会-  (2)  128  -128  2006/03
• 抗原提示細胞への抗原蛋白質デリバリーにおけるγ‐PGAナノ粒子の有用性

  小田淳史; 吉川友章; 丹羽貴子; 松尾一彦; 萱室裕之; 堤康央; 赤木隆美; 明石満; 岡田直貴; 中川晋作  日本薬学会年会要旨集  126年会-  (2)  128  -128  2006/03
• 両親媒化ポリグルタミン酸を用いた新規生分解性ワクチンキャリアの開発と抗腫ようワクチンへの応用―3

  飯田恵介; 吉川友章; 小田淳史; 丹羽貴子; 松尾一彦; 萱室裕之; 堤康央; 赤木隆美; 明石満; 中川晋作  日本免疫学会総会・学術集会記録  35-  129  -129  2005/11
• 両親媒化ポリグルタミン酸を用いた新規生分解性ワクチンキャリアの開発と抗腫ようワクチンへの応用―1

  吉川友章; 小田淳史; 丹羽貴子; 飯田恵介; 松尾一彦; 萱室裕之; 堤康央; 赤木隆美; 明石満; 中川晋作  日本免疫学会総会・学術集会記録  35-  128  -128  2005/11
• 変異型抗アポトーシス蛋白質Bcl‐xFNK発現樹状細胞を用いた抗腫よう効果に関する検討

  丹羽貴子; 吉川友章; 小田淳史; 飯田恵介; 松尾一彦; 萱屋裕之; 岡田直貴; 堤康央; 水口裕之; 中川晋作  日本免疫学会総会・学術集会記録  35-  120  -120  2005/11
• 両親媒化ポリγ-グルタミン酸を用いた新規生分解性ナノキャリアの開発と抗腫瘍ワクチンへの応用(2)

  小田 淳史; 吉川 友章; 丹羽 貴子; 飯田 恵介; 松尾 一彦; 萱室 裕之; 堤 康央; 赤木 隆美; 明石 満; 中川 晋作  日本免疫学会総会・学術集会記録  35-  128  -128  2005/11
• ワクチンキャリアとしてのポリアミノ酸由来生分解性ナノ粒子の有用性評価(1)

  吉川 友章; 小田 淳史; 丹羽 貴子; 飯田 恵介; 松尾 一彦; 下川 摩里子; 堤 康央; 赤木 隆美; 明石 満; 中川 晋作  Drug Delivery System  20-  (3)  362  -362  2005/05
• 活性増強変異型抗アポトーシス蛋白質Bcl-xFNK発現樹状細胞を用いた腫瘍ワクチン療法

  丹羽 貴子; 吉川 友章; 小田 淳史; 飯田 恵介; 松尾 一彦; 下川 摩里子; 岡田 直貴; 堤 康央; 水口 裕之; 中川 晋作  Drug Delivery System  20-  (3)  363  -363  2005/05
• ワクチンキャリアとしてのポリアミノ酸由来生分解性ナノ粒子の有用性評価(2)

  小田 淳史; 吉川 友章; 丹羽 貴子; 飯田 恵介; 松尾 一彦; 下川 摩里子; 堤 康央; 赤木 隆美; 明石 満; 中川 晋作  Drug Delivery System  20-  (3)  363  -363  2005/05

Awards & Honors

• 2011 日本薬学会近畿支部 日本薬学会近畿支部奨励賞（医療薬）
   感染症予防対策に資する経皮ワクチン製剤 (貼るワクチン) の開発 

  受賞者: 松尾一彦
• 2010 ファーマバイオフォーラム2010 優秀発表賞
   

  受賞者: 松尾一彦

Research Grants & Projects

• ケモカインCCL28の好酸球を介したメラノーマ腫瘍免疫における役割

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2023/04 -2026/03 

  Author : 中山 隆志; 原 雄大; 松尾 一彦
• 乾癬におけるケモカイン受容体CCR4を介したTh17細胞増殖の病理的役割の解明

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2020/04 -2023/03 

  Author : 中山 隆志; 松尾 一彦

   

  乾癬の発症には、Th17細胞が重要な役割を果たすことが知られている。ケモカイン受容体CCR4は、Th2細胞に発現し、Th2細胞の遊走を介してアトピー性皮膚炎等のアレルギー性疾患の発症に寄与している。近年、このCCR4がTh17細胞にも発現していることが明らかとなった。しかしながら、乾癬におけるCCR4の関与については不明である。本申請課題では、乾癬におけるCCR4を介したTh17細胞の遊走制御機構の解析を通じて、CCR4の乾癬の発症における役割を追究する。 前年度、イミキモド長期塗布により乾癬様病態を誘発したところ、野生型マウスと比べ、CCR4欠損マウスでは病態の軽減および病変部へのTh17細胞の浸潤の減少が認められた。 本年度は、CCR4の選択的阻害薬の投与による乾癬病態の変化について解析した。CCR4阻害薬compound22の2日に1回の投与により、臨床スコア（皮膚肥厚、紅斑、鱗屑）の軽減、病変皮膚および所属リンパ節でのTh17細胞の減少、乾癬関連遺伝子（IL-17A、IL-22、IL-23、STAT3、Keratin 14）の減少がみられた。以上より、CCR4の阻害が乾癬の治療戦略となる可能性が示された。
• Memory CTL-inducing vaccine sistem targeting P2 recepors

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2020/04 -2023/03 

  Author : 松尾 一彦; 中山 隆志

   

  本研究の目的は、P2受容体が粘膜特有のCD70陽性樹状細胞に発現すること、また、メモリーCTLの生存維持に関与することに着目し、P2受容体を介したエフェクター/メモリーCTL誘導およびその維持機構を解明し、P2受容体のアゴニストである加水分解性抵抗性APTのワクチンアジュバントとしての有用性を検証することである。 本年度は、加水分解抵抗性ATPによって誘導されたエフェクターあるいはメモリーCTLが抗腫瘍活性を示すかどうかについてin vivo担癌モデルマウスを用いて検討した。モデル抗原OVAと加水分解抵抗性ATPを経鼻投与し、エフェクター期およびメモリー期にOVA発現腫瘍細胞 (E.G7-OVA)を皮内に接種した。経日的に腫瘍体積をモニタリングした結果、加水分解抵抗性ATPを併用した場合において、有意な腫瘍増殖抑制効果を認められた。さらに、この効果はP2受容体の阻害剤であるスラミンの投与によって消失した。これらの結果から、加水分解性抵抗性ATPによって誘導されたCTLによって有意な抗腫瘍効果を示すことが明らかとなり、加水分解抵抗性ATPは機能的なCTLを誘導できるアジュバントとしての活性を有することを示した。
• Identification of a novel receptor for ELC/CCL19 and its role in psoriasis

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2017/04 -2020/03 

  Author : Nakayama Takashi

   

  ELC/CCL19 is a functional ligand for CCR7, which is mainly expressed by naive T and B cells. In the present study, we found that ELC/CCL19 is also a functional ligand for GPCR#13, which is broadly expressed by effector cells such as NK cells and monocytes. We revealed that ELC/CCL19 efficiently induced cell migration in murine L1.2 cells stably expressing GPCR#13 (L1.2-GPCR#13) as well as in L1.2-CCR7. Furthermore, In chemotaxis assays using human PBMCs, ELC/CCL19 attracted not only naive T cells but also CD16(+) NK cells and CD14(+) monocytes. In addition, ELC/CCL19-mediated cell migration was suppressed by treatment with a GPCR#13 antagonist. In mouse psoriasis model, intradermal injection of ELC/CCL19 recruited GPCR#13(+)/CCR7(-) effector cells in psoriasis-like skin lesions and exacerbated psoriasis-like inflammation. These results suggest that ELC/CCL19 another agonist for GPCR#13 and may play an important role in psoriasis by recruiting GPCR#13-expressing effector cells.
• Establishment of skin inflammation drug to accumulate high-functional regulatory T cells by single-cell gene expression analysis

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015/04 -2017/03 

  Author : Ikebuchi Ryoyo; TOMURA Michio; KUSUMOTO Yutaka; MORIYA Taiki; TERAGUCHI Shunsuke; Alexis Vandenbon; NAKAYAMA Takashi; MATSUO Kazuhiko

   

  We identified several regulatory T cell (Treg) subsets in inflamed skin tissue of mouse line expressing photoconvertible protein KikGR, by which we can distinguish skin-coming and -remaining lymphocytes, by multi-parameter single-cell gene and protein expression analysis. Each subset expressed each set of functional and migration-related molecules and showed different capabilities to remain in inflamed skin. We distinguished skin-coming and -remaining Tregs without KikGR expression data by multi-parameter single-cell expression analysis of functional and migration-related molecules. We also tried to identify master molecules of Treg subset differentiation and establish method to collect the Treg subsets. This research suggests that Tregs expressing different functional molecules showed different migration status in inflamed tissues.
• Screening of natural medicines with chemokine receptor antagonists for allergy therapy

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2014/04 -2017/03 

  Author : NAKAYAMA Takashi

   

  Chemokine receptors CCR3 and CCR4 have been paid attention as potent therapeutic targets for allergic diseases. First, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4. Thus, we examined inhibitory effects of ephedrine, a major component of Ephedra Herb. However, ephedrine exhibited little effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. Ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. Taken together, our data suggest that these crude drugs/herbs might be useful sources to develop new drugs targeting Th2-mediated allergic diseases.
• Development of adjuvants for CTL induction using high active form of lymphotactin/XCL1

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2014/04 -2017/03 

  Author : MATSUO Kazuhiko

   

  Recent studies have indicated that targeting antigens to XCR1, a chemokine receptor selectively expressed on cross-presenting dendritic cells using antigen fused to XCL1/Lymphotactin, an XCR1 ligand, represents an effective induction of CD8+ T cell response. In this study, we generate a high active form of XCL1 (XCL1-CC3) and investigate in vivo adjuvant efficacy. Wild-type XCL1 (XCL1-WT) have higher cell migration activity and calcium mobilization activity than XCL1-CC3. When intradermally injected with ovalbumin as a model antigen, both XCL1-WT and XCL1-CC3 induced potent CD8+ T cell responses and XCL1-CC3 showed more effective CD8+ T cell-mediated antitumor immunity than XCL1-WT. In addition, XCL1-CC3 enhanced an accumulation of CD103+XCR1+ cross-presenting dendritic cells rather than XCL1-WT. The present results indicate that XCL1-CC3 has potential to induce more efficient CD8+ T cells responses as CTL-inducing vaccine adjuvant than XCL1-WT.
• Development of transcutaneous immunization system for Alzheimer's disease

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2012/04 -2014/03 

  Author : MATSUO Kazuhiko

   

  Vaccine therapy for Alzheimer's disease (AD) based on the amyloid cascade hypothesis has recently attracted attention for treatment of AD. Injectable immunization of amyloid beta peptide (Ab) as antigens showed therapeutic efficacy; therefore, a clinical trial was conducted. However, the clinical trial was stopped due to the incidence of meningoencephalitis caused by excess activation of Th1 cells infiltrating the brain as a serious adverse reaction. Because recent studies have suggested that transcutaneous immunization (TCI) is likely to elicit Th2-dominant immune responses, in this study, we investigated the vaccine efficacy of TCI against AD using a novel dissolving microneedle array (MicroHyala; MH). Our TCI induced anti-Ab1-42 immune responses by simple and low-invasive application of Ab-containing MH to the skin. Unfortunately, this TCI resulted in little significant improvement in cognitive function and Th2-dominant immune responses, suggesting the need for further modification.

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