1999 Fiscal Year Annual Research Report

粘膜ワクチンへ向けての新しい粘膜アジュバンドの開発と解析

Research Project

Project/Area Number	10044284
Research Institution	Osaka University
Principal Investigator	清野宏大阪大学, 微生物病研究所, 教授 (10271032)
Co-Investigator(Kenkyū-buntansha)	廣井隆親大阪大学, 微生物病研究所, 助手 (80228824) 高橋一郎大阪大学, 微生物病研究所, 講師 (20206791)
Keywords	粘膜免疫システム / 粘膜ワクチン / 粘膜アジュバンド / 粘膜免疫調節因子 / 無毒化変異型CT / 経口ワクチン / 経鼻ワクチン / IgA
Research Abstract	次世代ワクチンとして期待されている経口・経鼻ワクチンの実現化に向けて、その効果をより高める粘膜免疫調節因子/粘膜アジュバントの開発が不可欠である。そこで、粘膜アジュバントとしてよく知られているコレラ毒素(CT)のヒトヘの応用をふまえて、S61FとE112Kと呼ばれる無毒化した変異型コレラ毒素(mCT)を開発し検討をくわえてきた。ワクチン抗原(例:破傷類毒素や肺炎球菌PspA)とmCTを併用して経鼻免疫すると、Th2型主導による感染阻止効果のある中和抗体の誘導ができることを証明した。さらにmCTのアジュバント効果発揮のメカニズムとして抗原提示細胞に作用してTh型・Th2型免疫応答誘導に深く関わっている補助活性化分子である、B7-1やB7-2の発現経路に影響を及ぼしている事がわかってきた。現在は、その効果がmCTのAもしくはBサブユニットのどちらに起因しているのか、キメラ分子を作成する事によって解折を試みている。さらに、mCTの他にサイトカインを粘膜アジュバントとして応用する試みをしており、抗原提示細胞由来のIL-12にその効果があるという興味ある結果を得た。Th1型応答誘導を惹起するし12をタンパク抗原と一緒に経鼻免疫すると興味ある事に抗原特異的IgA抗体を分泌液に誘導する。この事実は、細胞性と液性免疫両方を誘導出来ることを示唆しており、ウィルス感染を考えた時、有力な粘膜アジュバントとしてIL-12が使用出来るかもしれない。現在、その詳細なメカニズムについて解析を進めている。この様に日米の粘膜免疫に関連するエキスパートが協同研究体制を構築して活発な研究活動を推進することで、粘膜ワクチン開発に向けて興味ある貴重な新情報を提供している。

Research Products
(30 results)

All Other

All Publications (30 results)

[Publications] Boyaka, P.N., Kiyono, H. et al.: "Interleukin 12 is an effective adjuvant for induction of mucosal immunity"J. Immunol.. 162. 122-128 (1999)
[Publications] Marinaro, M., Kiyono, H. et al.: "Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin"J. Immunol.. 162. 114-121 (1999)
[Publications] Mbawuike, I.N., Kiyono, H. et al.: "IL-12 modulate IFN-γ synthesis and influenza-specific cytotoxic activity by human CD45RO+ but not CD45RA, CD8+ T cells"J. Infect. Dis.. 180. 1477-1486 (1999)
[Publications] Yamamoto, M., Kiyono, H. et al.: "Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant"J. Immunol.. 162. 7015-7021 (1999)
[Publications] Kurono, Y., Kiyono, H. et al.: "Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity"J. Infect. Dise.. 180. 122-132 (1999)
[Publications] van Ginkel., Kiyono, H. et al.: "IgA-deficiency with increased Th2-type cytokines in TGF-β1 knockout mice"J. Immunol.. 163. 1951-1957 (1999)
[Publications] Pascual, D.W., Kiyono, H. et al.: "Extracellular expression of recombinant enterotoxigenic colonization factor antigen I by Salmonella elicits distinct T helper 2 followed by T helper I cell responses"Infect. Immun.. 67. 6249-6256 (1999)
[Publications] McGhee, J.R., Kiyono, H. et al.: "Mucosal Thl-versus Th2-type responses for antibody or cell mediated immunity to SIV rhesus macaques"J. Infect. Dise.. 179. 5480-5484 (1999)
[Publications] Fujihashi, K., Kiyono, H. et al.: "γδT cells are not essential for oral tolerance induced by large dose of ovalbumin, while regulate IL-IO-mediated small dose systemic unresponsiveness"Int. Immunol.. 11. 1907-1916 (1999)
[Publications] Kweon, M-N., Kiyono, H. et al.: "Mucosally-induced systemic T cell unresponsiveness to ovalbumin requires CD40L-CD40 interactions"J. Immunol.. 162. 1904-0909 (1999)
[Publications] Dohi, T., Kiyono. H. et al.: "Hapten-induced colitis is associated with colonic patch hypertrophy and Th2 helper-type responses"J. Exp. Med.. 189. 1169-1179 (1999)
[Publications] Takahashi, I., Kiyono, H. et al.: "Clonal expansion of ββT cells in intestinal iruflammatory resions of T cell receptor a-chain deficient mice"J.Immunol.. 162. 1843-1850 (1999)
[Publications] Hiroi, T., Kiyono, H. et al.: "Deficiency of IL-5 receptor α chain selectively iniluences on the development of the commun mucosal immune system independent lgA producing B-1 cells in mucosal-associated tissues"J. Immunol.. 162. 821-828 (1999)
[Publications] Yanagita, M., Kiyono, H. et al.: "Nasopharyngeal-associated lymphoticular tissue (NALT) immunity : fimbriae-specific Th1 and Th2 cell-regulated lgA responses for the inhibition of bacterial attachment to epithelial cells and subsequent inflammatory cytokine production"J. Immunol.. 162. 3559-3565 (1999)
[Publications] Iijima, H., Kiyono, H. et al.: "Alteration of interleukin 4 production results in the inhibition of Th2 dominated inflammatory bowel disease in T cell receptor a chain-deficient mice"J. Exp. Med.. 190. 607-616 (1999)
[Publications] Host, D.F., Kiyono, H. et al.: "A double-blind. placebo-controlled study of Mycobacterium-specific human immune responses induced by intradermal bacille Calmette-Guerin vaccination"J. Lab. Clin. Med.. 134. 244-252 (1999)
[Publications] Tori, M., Kiyono, H. et al.: "Significant role of intragaft lymphoid tissues in preventing insulin-dependent diabetes mellitus recurrence in whole pancreaticoduodenal transplantation"Micro Surgery. 19. 338-343 (1999)
[Publications] Sugimoto, M., Kiyono, H. et al.: "Lymphocyte activation is attenuated by stellate ganglion block"Regional Anethesia and pain Medicine.. 24. 30-35 (1999)
[Publications] Tori, M., Kiyono, H. et al.: "IL-4 production in JDDM-nonrecurrent pancreas-transplanted BB rats with donor-derived NKR-P1+ TCRαβ+(NKT) cells but not in IDDM-recurrent BB rats"Transplanation Proceeding. 31. 1940-1941 (1999)
[Publications] Saitoh-Inagawa, W., Kiyono, H. et al.: "Immunological characterization of lacrimal glands as a part of mucosal immune network"Invest. Ophthalmol.. 41. 138-144 (2000)
[Publications] Higichi, K., Kiyono, H. et al.: "Comparison of inhibitory effects of intranasal and oral administration of bovine type II collagen on collagen induced arthritis in DBA1/J mice"J. Rheumato.. (in press). (2000)
[Publications] Simeka, J.W., Kiyono, H. et al.: "Nasal immunization with protein and cholera toxin as adjuvant results in an IgE-associated inflammatory response in lugs"Infect. Immun.. (in press). (2000)
[Publications] McGhee, J.R. and Klyono, H.: "The Mucosal immune system. In : Fundamental Immunology 4th Edition, Paul. W.E. (ed)"Lippincott-Racen Press, Philadelphia. 37 (1999)
[Publications] James, S.P. and Kiyono, H.: "Gastrointestinal and mucosal T cells. In : Mucosal Immunology, Ogra. P.L. et al. (eds)"Academic Press, San Diego.. 16 (1999)
[Publications] Hiroi, T., Kiyono, H. et al.: "L-5R+. B-1 cells : Are they CMIS independent B cells for mucosal IgA plasma cells"Mucosal Immunol. Update. 3 (1999)
[Publications] Boyaka, P.N., Kiyono, H. et al.: "Strategies for mucosal vaccine development"Am. J. Trop. Med. Hyg.. 3545 (1999)
[Publications] Takahashi, I., Kiyono, H. et al.: "Biochemical characterization of a population of CD4+, α-β+T cells in TCR-α mutant mice with inflammatory bowel diseases"FALK Proceeding. 5 (1999)
[Publications] Yamamoto M and Kryono, H.: "Role of γδT cells in mucosal intranet."Allergol. Intem.. 5 (1999)
[Publications] Yamamoto, M. and Kiyono, H.: "Immunoregulatory functions of mucosal γδT cells"Microbes and Infection.. 6 (1999)
[Publications] Takahashi, I. and Kiyono, H.: "Gut as the largest immunologic tissue"JPEN J . Parenter Enteral Nutr.. 6 (1999)

1999 Fiscal Year Annual Research Report

粘膜ワクチンへ向けての新しい粘膜アジュバンドの開発と解析

Principal Investigator

清野 宏 大阪大学, 微生物病研究所, 教授 (10271032)

Research Products

[Publications] Boyaka, P.N., Kiyono, H. et al.: "Interleukin 12 is an effective adjuvant for induction of mucosal immunity"J. Immunol.. 162. 122-128 (1999)

[Publications] Marinaro, M., Kiyono, H. et al.: "Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin"J. Immunol.. 162. 114-121 (1999)

[Publications] Mbawuike, I.N., Kiyono, H. et al.: "IL-12 modulate IFN-γ synthesis and influenza-specific cytotoxic activity by human CD45RO+ but not CD45RA, CD8+ T cells"J. Infect. Dis.. 180. 1477-1486 (1999)

[Publications] Yamamoto, M., Kiyono, H. et al.: "Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant"J. Immunol.. 162. 7015-7021 (1999)

[Publications] Kurono, Y., Kiyono, H. et al.: "Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity"J. Infect. Dise.. 180. 122-132 (1999)

[Publications] van Ginkel., Kiyono, H. et al.: "IgA-deficiency with increased Th2-type cytokines in TGF-β1 knockout mice"J. Immunol.. 163. 1951-1957 (1999)

[Publications] Pascual, D.W., Kiyono, H. et al.: "Extracellular expression of recombinant enterotoxigenic colonization factor antigen I by Salmonella elicits distinct T helper 2 followed by T helper I cell responses"Infect. Immun.. 67. 6249-6256 (1999)

[Publications] McGhee, J.R., Kiyono, H. et al.: "Mucosal Thl-versus Th2-type responses for antibody or cell mediated immunity to SIV rhesus macaques"J. Infect. Dise.. 179. 5480-5484 (1999)

[Publications] Fujihashi, K., Kiyono, H. et al.: "γδT cells are not essential for oral tolerance induced by large dose of ovalbumin, while regulate IL-IO-mediated small dose systemic unresponsiveness"Int. Immunol.. 11. 1907-1916 (1999)

[Publications] Kweon, M-N., Kiyono, H. et al.: "Mucosally-induced systemic T cell unresponsiveness to ovalbumin requires CD40L-CD40 interactions"J. Immunol.. 162. 1904-0909 (1999)

[Publications] Dohi, T., Kiyono. H. et al.: "Hapten-induced colitis is associated with colonic patch hypertrophy and Th2 helper-type responses"J. Exp. Med.. 189. 1169-1179 (1999)

[Publications] Takahashi, I., Kiyono, H. et al.: "Clonal expansion of ββT cells in intestinal iruflammatory resions of T cell receptor a-chain deficient mice"J.Immunol.. 162. 1843-1850 (1999)

[Publications] Hiroi, T., Kiyono, H. et al.: "Deficiency of IL-5 receptor α chain selectively iniluences on the development of the commun mucosal immune system independent lgA producing B-1 cells in mucosal-associated tissues"J. Immunol.. 162. 821-828 (1999)

[Publications] Iijima, H., Kiyono, H. et al.: "Alteration of interleukin 4 production results in the inhibition of Th2 dominated inflammatory bowel disease in T cell receptor a chain-deficient mice"J. Exp. Med.. 190. 607-616 (1999)

[Publications] Host, D.F., Kiyono, H. et al.: "A double-blind. placebo-controlled study of Mycobacterium-specific human immune responses induced by intradermal bacille Calmette-Guerin vaccination"J. Lab. Clin. Med.. 134. 244-252 (1999)

[Publications] Tori, M., Kiyono, H. et al.: "Significant role of intragaft lymphoid tissues in preventing insulin-dependent diabetes mellitus recurrence in whole pancreaticoduodenal transplantation"Micro Surgery. 19. 338-343 (1999)

[Publications] Sugimoto, M., Kiyono, H. et al.: "Lymphocyte activation is attenuated by stellate ganglion block"Regional Anethesia and pain Medicine.. 24. 30-35 (1999)

[Publications] Tori, M., Kiyono, H. et al.: "IL-4 production in JDDM-nonrecurrent pancreas-transplanted BB rats with donor-derived NKR-P1+ TCRαβ+(NKT) cells but not in IDDM-recurrent BB rats"Transplanation Proceeding. 31. 1940-1941 (1999)

[Publications] Saitoh-Inagawa, W., Kiyono, H. et al.: "Immunological characterization of lacrimal glands as a part of mucosal immune network"Invest. Ophthalmol.. 41. 138-144 (2000)

[Publications] Higichi, K., Kiyono, H. et al.: "Comparison of inhibitory effects of intranasal and oral administration of bovine type II collagen on collagen induced arthritis in DBA1/J mice"J. Rheumato.. (in press). (2000)

[Publications] Simeka, J.W., Kiyono, H. et al.: "Nasal immunization with protein and cholera toxin as adjuvant results in an IgE-associated inflammatory response in lugs"Infect. Immun.. (in press). (2000)

[Publications] McGhee, J.R. and Klyono, H.: "The Mucosal immune system. In : Fundamental Immunology 4th Edition, Paul. W.E. (ed)"Lippincott-Racen Press, Philadelphia. 37 (1999)

[Publications] James, S.P. and Kiyono, H.: "Gastrointestinal and mucosal T cells. In : Mucosal Immunology, Ogra. P.L. et al. (eds)"Academic Press, San Diego.. 16 (1999)

[Publications] Hiroi, T., Kiyono, H. et al.: "L-5R+. B-1 cells : Are they CMIS independent B cells for mucosal IgA plasma cells"Mucosal Immunol. Update. 3 (1999)

[Publications] Boyaka, P.N., Kiyono, H. et al.: "Strategies for mucosal vaccine development"Am. J. Trop. Med. Hyg.. 3545 (1999)

[Publications] Takahashi, I., Kiyono, H. et al.: "Biochemical characterization of a population of CD4+, α-β+T cells in TCR-α mutant mice with inflammatory bowel diseases"FALK Proceeding. 5 (1999)

[Publications] Yamamoto M and Kryono, H.: "Role of γδT cells in mucosal intranet."Allergol. Intem.. 5 (1999)

[Publications] Yamamoto, M. and Kiyono, H.: "Immunoregulatory functions of mucosal γδT cells"Microbes and Infection.. 6 (1999)

[Publications] Takahashi, I. and Kiyono, H.: "Gut as the largest immunologic tissue"JPEN J . Parenter Enteral Nutr.. 6 (1999)

清野宏大阪大学, 微生物病研究所, 教授 (10271032)