1998 年度実績報告書

粘膜ワクチンへ向けての新しい粘膜アジュバントの開発と解析

研究課題

研究課題/領域番号	10044284
研究種目	国際学術研究
応募区分	共同研究
研究機関	大阪大学
研究代表者	清野宏大阪大学, 微生物病研究所, 教授 (10271032)
研究分担者	藤橋浩太郎アラバマ大学, バーミングハム校, 助教授 MCGHEE Jerry アラバマ大学, バーミングハム校, 教授山本正文日本大学, 松戸歯学部, 講師 (80210558) 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)
キーワード	粘膜ワクチン / 粘膜アジュバント / 粘膜免疫調節因子 / 粘膜免疫 / 経鼻ワクチン / 経口ワクチン / IgA
研究概要	感染症に対する次世代ワクチン開発を考えたとき、第一線のバリアーとして作用する分泌型IgAを代表とする粘膜免疫の誘導が重要なポイントとなってくる。そこで本国際学術協同研究プロジェクトでは、抗原特異的IgA抗体誘導を効果的に増強する粘膜免疫活性化因子・粘膜アジュバントを開発する為の粘膜免疫に関連する基礎データを収集することを目的としている。本研究班は粘膜アジュバントととしてよく知られているコレラ毒素(CT)が効果的にIgA誘導サイト力イン(IL-5,IL-6)を産生するTh2細胞を活性化して、抗原特異的IgAの誘導を高めることを解明してきた。しかしながら、CTを粘膜アジュバントととしてヒトに使用することはその毒性から不可能である。そこで、国立国際医療センターとアラバマ大学の研究グループと協力して毒性活性部位のADP-リボシルトランスフェラーゼのアミノ酸置換により無毒化変異毒素(mCT)の開発に成功している。このmCT(S61FとE112K)を粘膜アジュバントとして肺炎球菌の共通膜表面タンパク抗原として注目されている。PspAと混合して実験用マウスに経鼻免疫すると抗体価の高い抗原特異的IgGとIgAが血清と鼻洗浄液に誘導された。さらに、鼻粘膜固有層や肺にPspA特異的抗体産生細胞が誘導されていることを確認している。呼吸器系の組織に抗原特異的IgA産生細胞を積極的に誘導するPspA特異的Th2細胞が誘導されていることを細胞とmRNA両方のレベルで解析している。さらに注目すべき結果は、経鼻免疫されたマウスには感染免疫が成立しており、約80%のマウスを肺炎球菌の感染から防ぐ事ができた。この結果はmCTを併用した粘膜ワクチン開発へ向けて貴重な新情報を提供している。

研究成果

(35件)

すべてその他

すべて文献書誌 (35件)

[文献書誌] Yamamoto,M.,Kiyono,H.et al.: "A nontoxic adjuvant for mucosal immunity to pneumucoccal surface protein A." J.Immunol.161. 4115-4121 (1998)
[文献書誌] Imaoka,K.,Kiyono,H.et al: "Nasal immunization of non-human primates with simian immunodeficiency virus p55gag and cholera toxin adjuvant induced Th1/Th2 help for anti-^viral immunity." J.Immunol.161. 5952-5958 (1998)
[文献書誌] Hiroi,T.,Kiyono,H.et al.: "Nasal immune system : Distinctive Th0 and Th1/Th2 type environments in murine nasal associated lvmohoid tissues and nasal passage respectively" Eur.J.Immunol.28. 3346-3353 (1998)
[文献書誌] VanCott,J.L.,Kiyono,H.et al.: "Regulation of host immune responses by modification of Salmonella virulence gene." Nature Medicine.4. 1247-1352 (1998)
[文献書誌] Kawabata,S.,Kiyono,H.et al: "Induction of polarized Th2 cytokine expressio for p27-specific IgA B cell responses after immunization with antigen in rhesus macaques." J.Infect.Dise.177. 26-33 (1998)
[文献書誌] Kawabata,S.,Kiyono H.et al: "Unique characteristics of intraepithelial lymphocytes from villi tip and cript portions of the small intestine." Gastroenterology. 115. 866-8* (1998)
[文献書誌] Lu,X.,Kiyono,H.et al: "Targeted lymph node immunizatio with whole-inactivated SIV or envelope and core subunit antigen vaccines dose not reliably protect rhesus macaques from vaginal challenge with SIV" AIDS. 12(1). 1-10 (1998)
[文献書誌] Harris,P.R.,Kiyono,H.et al: "Recombinant Helicobacter pylori urease activates primary mucosal macrophages." J.Infect.Dis.178(5). 1516-1520 (1998)
[文献書誌] Wikox,C.M.,Kiyono,H.et al: "High mucosal levels of tumor necrosis factor-α mRNA are associated with cytomegalovirus esphagitis." Gastroenterology. 114. 77-82 (1998)
[文献書誌] Nguyen,H.H.,Kiyono,H.et al: "Influenza virus-ingected epithelial cells present viral antigen to antigen-specific CD8^+ cytotoxic T lvmphocvtes(CTL)." J.Virology. 72. 4534-4536 (1998)
[文献書誌] Yuki,Y.,Kiyono,H.et al: "Human milk proteins including secretory IgA fail to elicit tolerance after feedig." Intern.Immunol.10. 537-545 (1998)
[文献書誌] Yamamoto,M.,Kiyono,H.et al: "Mucosal intranet : intestinal epithelial cells down regulate intraepoithelial but not peripheral T lymphocytes." J.immunol.160. 2188-2196 (1998)
[文献書誌] Kweon,M-N.,Kiyono,H.et al: "The role of Th1 cells in tolerance:lack of mucosally-induced unresponsiveness in interferon-gamma knockout mice." J.Immunol.160. 1687-1696 (1998)
[文献書誌] Sugimoto,M.,Kiyono,H.et al: "Upregulation of fas ligand(Fas L)mRNA expression in peripheral blood mononuclear cells (PBMC)after major surgery." Clin.Exp.Immunol.112. 120-125 (1998)
[文献書誌] Shimaoka,M.,Kiyono,H.et al: "High frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung iniurv." Crit.Care. 2. 35-39 (1998)
[文献書誌] Itoh,M.,Kiyono,H.et al: "Deletion of BST-1(CD157)gene impaired systemic TI-2 antigen-induced IgG3 and mucosal TD antigen-elicied IgA responses." J.Immunol.161. 3974-3983 (1998)
[文献書誌] Salbi,G.E.,Kiyono,H.et al: "Inglammatory mediators of the terminal dentition in adult and early onset periodontitis." J.Periodontal Res.33. 212-215 (1998)
[文献書誌] Shimaoka,M.,Kiyono,H.et al: "The influence of surgical stress on T cell:enhancement of early phase lymphocyte activation." Aneth.Analg.87. 1431-1433 (1998)
[文献書誌] Takahashi,I.,Kiyono,H.et al: "γδT cells:Bodyguards and/or spleepers in the gut." Chemical Immunol.71. 77-87 (1998)
[文献書誌] Boyaka,P.N.,Kiyono,H.et al: "Interleukin 12 is an effective adjuvant for induction of mucosal immunity." J.Immunol.162. 122-128 (1999)
[文献書誌] Marinaro,M.,Kiyono,H.et al: "Use of intranasal IL-12 to target predominatly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin." J.Immunol.162. 114-121 (1999)
[文献書誌] takahashi,I.,Kiyono,H.et al: "Clonal expansion of CD4^+TCR_<ββ>^+T cell in T cell receptor α-chain deficient mice by gut-derived antigens" J.Immunol.162. 1843-1850 (1999)
[文献書誌] Horii,T.,Kiyono,H.et al: "Deficiency of IL-5 receptor α chain selectively influences on the development of the comman mucosal immune system independent IgA producing B-1 cells in mucosal ssociated tissues." J.Immunol.162. 821-828 (1999)
[文献書誌] Tori,M.,Kiyono,H.et al: "The significant role of intragaft lymphoid tissues in preventing IDDM(insulin-dependent diabetes mellitus)recurrence in whole pancreaticoduodenal transplation." J.Micro Surgery.(in press). (1999)
[文献書誌] McGhee,J.R.,Kiyono,H.et al: "mucosal Th-1 versus Th2-type responses for antibody or cell mediated immunity to SIV rhesus macaques." J.Infect.Dise.(in press). (1999)
[文献書誌] Yanagita,M.,Kiyono,H.et al: "Nasopharyngeal-associated lymphoreticular tissue(NALT) immunity:fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachement to epithelial cells" J.Immunol.(in press). (1999)
[文献書誌] Kweon,M-N.,Kiyono,H.et al: "Mucosally-induced systemic T cell unresponsiveness to ovalbumin requires CD40L-CD40 interactions." J.Immunol.(in press). (1999)
[文献書誌] Kurono,Y.,Kiyono,H.et al: "Mucosal Solutions Advances in Mucosal Immunology." SMI,Maryland, 311-315 (1998)
[文献書誌] McGhee,J.R.,Kiyono,H.: "Fundamental Immunology 4th Edition" Lippincott-Raven Press,Philadelphia, 909-945 (1999)
[文献書誌] VanCott,J.L.,Kiyono,H.et al: "Importance of vaccine delivery mode on outcome of helper T subsets and cytokines for mucosal IgA responses." Recent Advances in Otitis Media (in press), (1999)
[文献書誌] Boyaka,P.N.,kiyono,H.et al: "Strategies for mucosal vaccine development" Toropical Medicine (in press), (1999)
[文献書誌] Takahashi,I.,Kiyono,H.et al: "Biochemical characterization of a population of CD4^+,α^+β T cells in TCR-α mutant mice with inflammatorv bowel diseases." FALK proceeding, 142-146 (1999)
[文献書誌] James,S.P.,Kiyono,H: "Mucosal Immunology" Academic Press, 381-396 (1999)
[文献書誌] Yamamoto,M.,Kiyono,H.: "γδT cells in mucosal intranet." Allergol.Intern. (in press), (1999)
[文献書誌] Yamamoto,M.,Kiyono,H.: "Immunoregulatory function of mucosal γδT cells" Annu.Inst.Pasture. (in press), (1999)

1998 年度 実績報告書

粘膜ワクチンへ向けての新しい粘膜アジュバントの開発と解析

研究代表者

清野 宏 大阪大学, 微生物病研究所, 教授 (10271032)

研究成果

[文献書誌] Yamamoto,M.,Kiyono,H.et al.: "A nontoxic adjuvant for mucosal immunity to pneumucoccal surface protein A." J.Immunol.161. 4115-4121 (1998)

[文献書誌] Imaoka,K.,Kiyono,H.et al: "Nasal immunization of non-human primates with simian immunodeficiency virus p55gag and cholera toxin adjuvant induced Th1/Th2 help for anti-^viral immunity." J.Immunol.161. 5952-5958 (1998)

[文献書誌] Hiroi,T.,Kiyono,H.et al.: "Nasal immune system : Distinctive Th0 and Th1/Th2 type environments in murine nasal associated lvmohoid tissues and nasal passage respectively" Eur.J.Immunol.28. 3346-3353 (1998)

[文献書誌] VanCott,J.L.,Kiyono,H.et al.: "Regulation of host immune responses by modification of Salmonella virulence gene." Nature Medicine.4. 1247-1352 (1998)

[文献書誌] Kawabata,S.,Kiyono,H.et al: "Induction of polarized Th2 cytokine expressio for p27-specific IgA B cell responses after immunization with antigen in rhesus macaques." J.Infect.Dise.177. 26-33 (1998)

[文献書誌] Kawabata,S.,Kiyono H.et al: "Unique characteristics of intraepithelial lymphocytes from villi tip and cript portions of the small intestine." Gastroenterology. 115. 866-8* (1998)

[文献書誌] Lu,X.,Kiyono,H.et al: "Targeted lymph node immunizatio with whole-inactivated SIV or envelope and core subunit antigen vaccines dose not reliably protect rhesus macaques from vaginal challenge with SIV" AIDS. 12(1). 1-10 (1998)

[文献書誌] Harris,P.R.,Kiyono,H.et al: "Recombinant Helicobacter pylori urease activates primary mucosal macrophages." J.Infect.Dis.178(5). 1516-1520 (1998)

[文献書誌] Wikox,C.M.,Kiyono,H.et al: "High mucosal levels of tumor necrosis factor-α mRNA are associated with cytomegalovirus esphagitis." Gastroenterology. 114. 77-82 (1998)

[文献書誌] Nguyen,H.H.,Kiyono,H.et al: "Influenza virus-ingected epithelial cells present viral antigen to antigen-specific CD8^+ cytotoxic T lvmphocvtes(CTL)." J.Virology. 72. 4534-4536 (1998)

[文献書誌] Yuki,Y.,Kiyono,H.et al: "Human milk proteins including secretory IgA fail to elicit tolerance after feedig." Intern.Immunol.10. 537-545 (1998)

[文献書誌] Yamamoto,M.,Kiyono,H.et al: "Mucosal intranet : intestinal epithelial cells down regulate intraepoithelial but not peripheral T lymphocytes." J.immunol.160. 2188-2196 (1998)

[文献書誌] Kweon,M-N.,Kiyono,H.et al: "The role of Th1 cells in tolerance:lack of mucosally-induced unresponsiveness in interferon-gamma knockout mice." J.Immunol.160. 1687-1696 (1998)

[文献書誌] Sugimoto,M.,Kiyono,H.et al: "Upregulation of fas ligand(Fas L)mRNA expression in peripheral blood mononuclear cells (PBMC)after major surgery." Clin.Exp.Immunol.112. 120-125 (1998)

[文献書誌] Shimaoka,M.,Kiyono,H.et al: "High frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung iniurv." Crit.Care. 2. 35-39 (1998)

[文献書誌] Itoh,M.,Kiyono,H.et al: "Deletion of BST-1(CD157)gene impaired systemic TI-2 antigen-induced IgG3 and mucosal TD antigen-elicied IgA responses." J.Immunol.161. 3974-3983 (1998)

[文献書誌] Salbi,G.E.,Kiyono,H.et al: "Inglammatory mediators of the terminal dentition in adult and early onset periodontitis." J.Periodontal Res.33. 212-215 (1998)

[文献書誌] Shimaoka,M.,Kiyono,H.et al: "The influence of surgical stress on T cell:enhancement of early phase lymphocyte activation." Aneth.Analg.87. 1431-1433 (1998)

[文献書誌] Takahashi,I.,Kiyono,H.et al: "γδT cells:Bodyguards and/or spleepers in the gut." Chemical Immunol.71. 77-87 (1998)

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

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

[文献書誌] takahashi,I.,Kiyono,H.et al: "Clonal expansion of CD4^+TCR_<ββ>^+T cell in T cell receptor α-chain deficient mice by gut-derived antigens" J.Immunol.162. 1843-1850 (1999)

[文献書誌] Horii,T.,Kiyono,H.et al: "Deficiency of IL-5 receptor α chain selectively influences on the development of the comman mucosal immune system independent IgA producing B-1 cells in mucosal ssociated tissues." J.Immunol.162. 821-828 (1999)

[文献書誌] Tori,M.,Kiyono,H.et al: "The significant role of intragaft lymphoid tissues in preventing IDDM(insulin-dependent diabetes mellitus)recurrence in whole pancreaticoduodenal transplation." J.Micro Surgery.(in press). (1999)

[文献書誌] McGhee,J.R.,Kiyono,H.et al: "mucosal Th-1 versus Th2-type responses for antibody or cell mediated immunity to SIV rhesus macaques." J.Infect.Dise.(in press). (1999)

[文献書誌] Yanagita,M.,Kiyono,H.et al: "Nasopharyngeal-associated lymphoreticular tissue(NALT) immunity:fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachement to epithelial cells" J.Immunol.(in press). (1999)

[文献書誌] Kweon,M-N.,Kiyono,H.et al: "Mucosally-induced systemic T cell unresponsiveness to ovalbumin requires CD40L-CD40 interactions." J.Immunol.(in press). (1999)

[文献書誌] Kurono,Y.,Kiyono,H.et al: "Mucosal Solutions Advances in Mucosal Immunology." SMI,Maryland, 311-315 (1998)

[文献書誌] McGhee,J.R.,Kiyono,H.: "Fundamental Immunology 4th Edition" Lippincott-Raven Press,Philadelphia, 909-945 (1999)

[文献書誌] VanCott,J.L.,Kiyono,H.et al: "Importance of vaccine delivery mode on outcome of helper T subsets and cytokines for mucosal IgA responses." Recent Advances in Otitis Media (in press), (1999)

[文献書誌] Boyaka,P.N.,kiyono,H.et al: "Strategies for mucosal vaccine development" Toropical Medicine (in press), (1999)

[文献書誌] Takahashi,I.,Kiyono,H.et al: "Biochemical characterization of a population of CD4^+,α^+β T cells in TCR-α mutant mice with inflammatorv bowel diseases." FALK proceeding, 142-146 (1999)

[文献書誌] James,S.P.,Kiyono,H: "Mucosal Immunology" Academic Press, 381-396 (1999)

[文献書誌] Yamamoto,M.,Kiyono,H.: "γδT cells in mucosal intranet." Allergol.Intern. (in press), (1999)

[文献書誌] Yamamoto,M.,Kiyono,H.: "Immunoregulatory function of mucosal γδT cells" Annu.Inst.Pasture. (in press), (1999)

1998 年度実績報告書

清野宏大阪大学, 微生物病研究所, 教授 (10271032)