松尾 一彦 (マツオ カズヒコ)

  • 薬学部 医療薬学科 准教授
Last Updated :2024/02/13

コミュニケーション情報 byコメンテータガイド

  • コメント

    細胞遊走制御因子ケモカインは、感染症や癌の病態発症に重要な役割を果たすことが知られています。私達は、ケモカイン系を標的とした感染症や癌に対する新規創薬・ワクチンの開発を目指しています。

研究者情報

学位

  • 博士(薬学)(2011年03月 大阪大学)

ホームページURL

科研費研究者番号

  • 70615921

J-Global ID

研究キーワード

  • 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   

現在の研究分野(キーワード)

    細胞遊走制御因子ケモカインは、感染症や癌の病態発症に重要な役割を果たすことが知られています。私達は、ケモカイン系を標的とした感染症や癌に対する新規創薬・ワクチンの開発を目指しています。

研究分野

  • ライフサイエンス / 感染症内科学
  • ライフサイエンス / 医療薬学

経歴

  • 2023年04月 - 現在  近畿大学薬学部 医療薬学科准教授
  • 2017年04月 - 2023年03月  近畿大学薬学部医療薬学科講師
  • 2012年04月 - 2017年03月  近畿大学薬学部医療薬学科助教
  • 2011年04月 - 2012年03月  大阪大学薬学研究科(研究院)特任研究員

研究活動情報

論文

  • Yuta Hara; Tatsuma Honzawa; Moeka Kitagawa; Ritsuki Sano; Kazuhiko Matsuo; Takashi Nakayama
    Journal of Pharmacological Sciences 153 3 89 - 93 2023年11月
  • Masako Sato; Kazuhiko Matsuo; Yoko Susami; Ayaka Yamashita; Haruko Hayasaka; Yuta Hara; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama
    International Immunology 35 9 437 - 446 2023年06月 
    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.
  • Tomonori Higuchi; Yumiko Hashida; Kazuhiko Matsuo; Kosuke Kitahata; Takako Ujihara; Ichiro Murakami; Takashi Nakayama; Masanori Daibata
    Cancer science 114 6 2622 - 2633 2023年03月 
    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.
  • 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年01月 
    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.
  • 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年08月 
    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.
  • 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年04月 
    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.
  • Kazuhiko Matsuo; Osamu Yoshie; Takashi Nakayama
    Cancers 13 23 2021年12月 
    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.
  • 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
    2021年10月 
    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 41 11 1018 - 1022 (株)北隆館 2021年10月 
    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)
  • 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年08月 
    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.
  • Kazuhiko Matsuo; Osamu Yoshie; Kosuke Kitahata; Momo Kamei; Yuta Hara; Takashi Nakayama
    Cancers 13 10 2021年05月 
    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 10 1 132 - 136 (株)北隆館 2021年05月 
    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)
  • 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年10月 
    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.
  • 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年09月 
    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.
  • Momo Kamei; Kazuhiko Matsuo; Haruka Imanishi; Yuta Hara; Ying-Shu Quen; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Naoki Okada; Takashi Nakayama
    J. Pharmacol. Sci. 143 3 182 - 187 2020年07月 [査読有り]
     
    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.
  • 松尾 一彦; 中山 隆志
    ファルマシア 56 4 309 - 313 (公社)日本薬学会 2020年04月 
    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.
  • 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 2019年12月 [査読有り]
     
    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.
  • Higuchi T; Matsuo K; Hashida Y; Kitahata K; Ujihara T; Taniguchi A; Yoshie O; Nakayama T; Daibata M
    Cancer letters 453 184 - 192 2019年07月 [査読有り]
     
    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.
  • 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 2019年01月 [査読有り]
     
    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.
  • 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 2019年01月 [査読有り]
     
    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.
  • Kosuke Kitahata; Kazuhiko Matsuo; Yuta Hara; Takanori Naganuma; Naoki Oiso; Akira Kawada; Takashi Nakayama
    Journal of pharmacological sciences 138 4 284 - 288 2018年12月 [査読有り]
     
    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.
  • 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 2018年08月 [査読有り]
     
    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.
  • 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 2018年03月 [査読有り]
     
    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.
  • 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 2018年01月 [査読有り]
     
    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.
  • 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年 [査読有り]
     
    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.
  • 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 7 1 7663  2017年08月 [査読有り]
     
    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.
  • 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 2016年08月 [査読有り]
     
    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.
  • Toshio Morikawa; Ikuko Hachiman; Kazuhiko Matsuo; Eriko Nishida; Kiyofumi Ninomiya; Takao Hayakawa; Osamu Yoshie; Osamu Muraoka; Takashi Nakayama
    JOURNAL OF NATURAL PRODUCTS 79 8 2005 - 2013 2016年08月 [査読有り]
     
    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).
  • Kazuhiko Matsuo; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 39 7 1201 - 1205 2016年07月 [査読有り]
     
    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.
  • Matsuo K; Nishiuma S; Hasegawa Y; Kawabata F; Kitahata K; Nakayama T
    Biological & pharmaceutical bulletin 39 6 1073 - 1076 2016年06月 [査読有り]
     
    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.
  • 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年 [査読有り]
     
    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.
  • Sachiko Hirobe; Hiroaki Azukizawa; Takaaki Hanafusa; Kazuhiko Matsuo; Ying-Shu Quan; Fumio Kamiyama; Ichiro Katayama; Naoki Okada; Shinsaku Nakagawa
    BIOMATERIALS 57 50 - 58 2015年07月 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Yayoi Yokota; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa
    Journal of Controlled Release 184 1 9  2014年06月 [査読有り]
  • Maiko Kato; Naoki Oiso; Tatsuki Itoh; Masako Sato; Kazuhiko Matsuo; Takashi Nakayama; Takao Satou; Akira Kawada
    JOURNAL OF DERMATOLOGY 41 5 459 - 461 2014年05月 [査読有り]
  • Matsuo K; Okamoto H; Kawai Y; Quan YS; Kamiyama F; Hirobe S; Okada N; Nakagawa S
    Journal of neuroimmunology 266 1-2 1 - 11 2014年01月 [査読有り]
     
    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.
  • Sachiko Hirobe; Hiroaki Azukizawa; Kazuhiko Matsuo; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Hiroshi Suzuki; Ichiro Katayama; Naoki Okada; Shinsaku Nakagawa
    PHARMACEUTICAL RESEARCH 30 10 2664 - 2674 2013年10月 [査読有り]
     
    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.
  • 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 120 5 767 - 783 2013年05月 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa
    Vaccine 31 19 2403 - 2415 2013年05月 [査読有り]
     
    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 28年会 208 - 208 (公社)日本薬剤学会 2013年04月
  • Kazuhiko Matsuo; Yumiko Ishii; Yasuaki Kawai; Yuki Saiba; Ying-Shu Quan; Fumio Kamiyama; Sachiko Hirobe; Naoki Okada; Shinsaku Nakagawa
    Journal of Pharmaceutical Sciences 102 6 1936 - 1947 2013年 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Yayoi Yokota; You Zhai; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa
    JOURNAL OF CONTROLLED RELEASE 161 1 10 - 17 2012年07月 [査読有り]
     
    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 28回 128 - 128 日本DDS学会 2012年06月
  • 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 160 3 495 - 501 2012年06月 [査読有り]
     
    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.
  • Sachiko Hirobe; Kazuhiko Matsuo; Ying-Shu Quan; Fumio Kamiyama; Hironori Morito; Hideo Asada; Yusuke Takaya; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa
    VACCINE 30 10 1847 - 1854 2012年02月 [査読有り]
     
    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.
  • Mukai Y; Yoshinaga T; Yoshikawa M; Matsuo K; Yoshikawa T; Matsuo K; Niki K; Yoshioka Y; Okada N; Nakagawa S
    Journal of immunology (Baltimore, Md. : 1950) 187 12 6249 - 6255 2011年12月 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Hideo Asada; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 12 1835 - 1840 2011年12月 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Naoki Okada; Shinsaku Nakagawa
    Nihon rinsho. Japanese journal of clinical medicine 69 9 1561 - 6 2011年09月 [査読有り]
     
    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.
  • 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 2011年06月 [査読有り]
  • 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 26 3 312 - 312 日本DDS学会 2011年05月
  • 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 32 11 2713 - 2724 2011年04月 [査読有り]
     
    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.
  • Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 4 586 - 589 2011年04月 [査読有り]
     
    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 131年会 4 188 - 188 (公社)日本薬学会 2011年03月
  • Kazuhiko Matsuo; Yumiko Ishii; Ying-Shu Quan; Fumio Kamiyama; Yohei Mukai; Yasuo Yoshioka; Naoki Okada; Shinsaku Nakagawa
    JOURNAL OF CONTROLLED RELEASE 149 1 15 - 20 2011年01月 [査読有り]
     
    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.
  • Matsuo K; Ishii Y; Matsuo K; Yoshinaga T; Akashi M; Mukai Y; Yoshioka Y; Okada N; Nakagawa S
    Biological & pharmaceutical bulletin 33 12 2003 - 2007 2010年12月 [査読有り]
     
    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年05月 [招待有り]
  • 「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 130年会 4 163 - 163 (公社)日本薬学会 2010年03月
  • 松尾 一彦; 岡田 直貴; 中川 晋作
    Drug Delivery System 25 1 8 - 14 日本DDS学会 2010年 
    皮膚の免疫機能を最大限に利用した経皮ワクチンは,注射に代わる簡便で安価かつ非侵襲的な新規ワクチン手法として期待されている.経皮ワクチンにおいては,抗原を表皮組織に存在する抗原提示細胞へと送達する基盤技術の確立が必須であり,その研究開発が精力的に行われている.
    本稿では,近年の経皮ワクチンデリバリー技術の研究動向についての解説を交えながら,筆者らが独自に開発した親水性ゲルパッチを用いた経皮ワクチンの研究成果について紹介する.
  • 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 131 2 113 - 120 2008年10月 [査読有り]
     
    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.
  • Tomoaki Yoshikawa; Naoki Okada; Atsushi Oda; Keisuke Matsuo; Kazuhiko Matsuo; Hiroyuki Kayamuro; Yumiko Ishii; Tomoyo Yoshinaga; Takami Akagi; Mitsuru Akashi; Shinsaku Nakagawa
    VACCINE 26 10 1303 - 1313 2008年03月 [査読有り]
     
    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.
  • 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 366 2 408 - 413 2008年02月 [査読有り]
     
    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.

書籍

  • 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 (担当:共著範囲:)エヌ・ティー・エス 2013年07月
  • Bio-Nanotechnology: A Revolution in Food, Biomedical and Health Sciences
    Kazuhiko Matsuo; Naoki Okada; Shinsaku Nakagawa (担当:共著範囲:)Wiley-Blackwell 2013年01月
  • 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 (担当:共著範囲:)シーエムシー出版 2012年03月
  • 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 (担当:共著範囲:)シーエムシー出版 2011年11月
  • 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 (担当:共著範囲:)シーエムシー出版 2011年07月
  • 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 (担当:共著範囲:)シーエムシー出版 2010年09月

MISC

受賞

  • 2011年 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年 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

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 中山 隆志; 原 雄大; 松尾 一彦
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 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。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 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。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 中山 隆志; 松尾 一彦
     
    本研究において研究代表者は、ケモカインELC/CCL19がGPCR#13受容体の新規の機能的リガンドであることを見出した。また、ELC/CCL19はGPCR#13に対して、既知受容体のCCR7と同程度のアゴニスト活性を持ち、CCR7を発現していないGPCR#13陽性のエフェクター細胞の遊走を担う機能的なリガンドであることを明らかにした。また、乾癬モデルマウスへのELC/CCL19の経皮投与により、病変部でのGPCR#13陽性エフェクター細胞の浸潤が増加し、乾癬病態が増悪した。以上の結果より、ELC/CCL19-GPCR#13系が乾癬の病態形成に重要な役割を果たしている可能性が示された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2015年04月 -2017年03月 
    代表者 : 池渕 良洋; 戸村 道夫; 楠本 豊; 守屋 大樹; 寺口 俊介; 中山 隆志; 松尾 一彦
     
    光変換蛋白質KikGRを発現するマウスによって同定可能な炎症皮膚に「来た」「留まった」制御性T細胞(Treg)を対象に、シングルセル遺伝子・蛋白質多因子発現解析を行い、異なるTreg機能分子を発現する複数のサブセットを同定した。サブセット間を比較すると、発現する遊走関連分子も、皮膚に「留まる」性質も異なった。機能分子と遊走関連分子の多因子発現解析により、KikGR発現データを用いずに皮膚に「来た」「留まった」Tregを区別した。Tregサブセットの分化責任因子の同定及び炎症皮膚への集積法の樹立も試みた。本研究により、異なる機能分子を発現するTregは異なる炎症組織間遊走を行うことが示唆された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 中山 隆志; 松尾 一彦
     
    これまでに研究代表者は和漢薬ライブラリーを用いて細胞遊走阻害活性を指標としたケモカインアンタゴニストの探索を行ってきた。本研究において、麻黄エキスがケモカイン受容体CCR3、CCR4、およびCCR8特異的なアンタゴニスト活性を示し、そのアンタゴニスト活性が麻黄エキスの酢酸エチル非可溶性分画に存在することを明らかとした。また、このアンタゴニスト成分による阻害活性にリガンド特異性はなく、受容体を直接阻害することが示唆された。 CCR3、CCR4、およびCCR8は、いずれもTh2細胞あるいは好酸球や好塩基球に選択的に発現することから、アレルギー性疾患において重要な役割を果たすと考えられる。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 松尾 一彦
     
    近年、ケモカイン受容体XCR1がCTL誘導に特化した樹状細胞に選択的に発現することが明らかとなり、XCR1のリガンドであるXCL1のCTL誘導アジュバントへの応用が期待されている。本研究では、XCL1の構造変異体 (XCL1-CC3) を作製し、XCL1-CC3が野生型XCL1-WTに比べて細胞遊走活性が向上することを明らかとした。また、in vivoにおいてXCL1-CC3は有意にCD103陽性樹状細胞を抗原投与部位に集積させ、OVA特異的CTL誘導を促進した。さらに、XCL1-CC3を併用投与したマウスにおいては非常に強力な抗腫瘍効果が認められた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2012年04月 -2014年03月 
    代表者 : 松尾 一彦
     
    アルツハイマー病 (AD) に対する新たな治療法としてワクチン療法が注目されている。これまでにアミロイドβペプチド (Aβ) を注射免疫する臨床試験が行われたが、Aβ反応性Th1細胞の過剰な活性化に起因する重篤な副作用を誘発したために頓挫した。申請者は、経皮免疫はTh2反応を優位に誘導するという知見から、自己溶解型マイクロニードルを応用した経皮免疫療法の開発を試みた。ADモデルマウスに経皮免疫を行うと、抗Aβ IgG抗体の誘導が確認された。しかし認知機能の改善効果は弱く、誘導された免疫応答は注射免疫と同じくTh1優位であることが判明し、副作用抑制を達成するには、本法の改良の必要性が示された。

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