1997 Fiscal Year Annual Research Report

感染防御におけるIL-12の役割

Research Project

Project/Area Number	09044265
Research Institution	The University of Tokyo
Principal Investigator	善本隆之東京大学, 医科学研究所, 助手 (80202406)
Co-Investigator(Kenkyū-buntansha)	辻守哉ニューヨーク大学, 医学部, 助教授成内秀雄東京大学, 医科学研究所, 教授 (10012741)
Keywords	IL-12 / マラリア / 感染防御 / 病態形成
Research Abstract	今年度は、強毒株P. berghei NK65とその弱毒株XATを用い、マラリア感染におけるIL-12の役割について解析した。弱毒株感染赤血球をマウスに投与すると、Parasitemiaの上昇後2-3週間で原虫は血中より除去される。この時Splenectomyを施したマウスでは原虫を除去できず死亡したことより、感染防御にかかわる臓器として脾臓を中心に検討を行った。まず、感染赤血球を投与後4-6日をピークにIL-12p40,IFN-γ,IL-4、IL-10 mRNAの発現が増強され、iNOS mRNAの発現増大やNK細胞の活性化も見られた。そこで、これらの中和抗体を投与すると、IL-12またはIFN-γの抗体により防御能が低下しParasitemiaが増大し続け死亡したことより、IL-12とIFN-γ産生が感染防御に重要であることが明らかとなった。さらに、抗IL-12抗体投与後、脾臓でのIFN-γ mRNAの発現増強が低下し、in vitroでの感染脾細胞からのIFN-γ産生も低下、iNOS mRNAの発現増強やNK活性化も低下した。これらのことより、感染によりIL-12発現が増大し、その結果NK細胞が活性化され、また、IFN-γ産生が増強されiNOSが誘導されることがマラリアの感染防御に重要であることが示された。一方、強毒株感染赤血球をマウスに投与すると、Parasitemiaは上昇し続け強い貧血になり2-3週間で死亡する。この時、弱毒株の時と同様に脾臓及び肝臓においてIL-12発現やIL-12に依存的なIFN-γ産生が誘導された。そこで、IL-12またはIFN-γの中和抗体を投与すると、弱毒株時とは逆に生存率が延長し、体重減少や血清GOTやGPT活性の上昇が抑制された。さらに、肝細胞の壊死が軽減され、肝傷害が抑えられていることがわかった。以上より、いずれの感染によってもIL-12発現が誘導されるが、弱毒株感染においては感染防御に、一方強毒株感染においてはむろしろ病態形成に関与するというIFN-γ産生を介したIL-12の二面性が示唆された。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] T. Yoshimoto: "IL-12 dependent mechanisms in the clearance of blood-stage murine malaria Plasmodium berghei XAT, an attenuated variant of Plasmodium berghei NK65." J. Infec. Dis.(in press).
[Publications] T. Yoshimoto: "Reduced Thl responeses in interleukin-12 p40 transgenic mice." J. Immunol.160. 588-594 (1998)
[Publications] T. Yoshimoto: "Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-κB." Eur. J. Immunol.27. 3461-3470 (1997)
[Publications] H. Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4." Eur. J. Immunol.(in pres).
[Publications] H. Nakano: "Regulation of T lymphocytes specific homing by a single factor in the peripheral lymph nodes." Eur. J. Immunol.27. 215-221 (1997)
[Publications] Y. Miyahira: "Recombinant-viruses expressing a human malaria antigen elicited protective cellular and humoral responses in mice." Proc. Natl. Acad. Sci. USA.(In press).
[Publications] E. G. Rodrigues: "Efficient induction of protective anti-malaria immunity by recombinant adenovirus." Vaccine. (In press.).
[Publications] W. Born: "Establishment of murine T cell lines, T cell clones, hybridomas and transfectomas." Methods in Microbiology (Academic Press, New York) 25 :.
[Publications] E. G. Rodrigues: "Single immunizing dose of recombinant adenovirus efficiently induces CD8^+T cell-mediated protective immunity against malaria." J. Immunol.158. 1268-1274 (1997)
[Publications] O. Igarashi: "IL-12R expression and accumulation of IL-12Rβ1 and IL-12Rβ2 mRNAs in CD4^+T cells by the costimulation with B7-2 molecules." J. Immunol.in press.
[Publications] T. Kato: "Diffeential effects of LPS and CD40 ligand stimulations on the induction of IL-12 production by dendritic cells and macrophages." Cell. Immunol.181. 59-67 (1997)
[Publications] T. Kato: "Costimulatory effect of IL-12 on the activation of naive, memory CD4+T cells, and Thl clone." Cell. Immunol.176. 50-58 (1997)
[Publications] M. Utsuyama: "Impairment of signal transduction in T cells from old mice." Mech. Ageing Develop.93. 131-144 (1997)
[Publications] H. Nakano: "A novel mutant gene involved in T lymphocyte specific homing into peripheral lymphoid organs on murine chromosome 4." Blood. (in press).
[Publications] R. Hakamada: "Expression and costimulatory function of B7-2 on murine CD4^+T cells." Eur. J. Immunol. (in press).
[Publications] S. Yamanouchi: "T cell activation antigen Ly6C induced on CD4^+Thl cells mediates an inhibitory signal for secretion of IL-2 and proliferation in peripheral immune responsse." Eur. J. Immunol.(in press).

1997 Fiscal Year Annual Research Report

感染防御におけるIL-12の役割

Principal Investigator

善本 隆之 東京大学, 医科学研究所, 助手 (80202406)

Research Products

[Publications] T. Yoshimoto: "IL-12 dependent mechanisms in the clearance of blood-stage murine malaria Plasmodium berghei XAT, an attenuated variant of Plasmodium berghei NK65." J. Infec. Dis.(in press).

[Publications] T. Yoshimoto: "Reduced Thl responeses in interleukin-12 p40 transgenic mice." J. Immunol.160. 588-594 (1998)

[Publications] T. Yoshimoto: "Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-κB." Eur. J. Immunol.27. 3461-3470 (1997)

[Publications] H. Nagase: "Novel mutant mice secreting soluble CD4 without expression of membrane-bound CD4." Eur. J. Immunol.(in pres).

[Publications] H. Nakano: "Regulation of T lymphocytes specific homing by a single factor in the peripheral lymph nodes." Eur. J. Immunol.27. 215-221 (1997)

[Publications] Y. Miyahira: "Recombinant-viruses expressing a human malaria antigen elicited protective cellular and humoral responses in mice." Proc. Natl. Acad. Sci. USA.(In press).

[Publications] E. G. Rodrigues: "Efficient induction of protective anti-malaria immunity by recombinant adenovirus." Vaccine. (In press.).

[Publications] W. Born: "Establishment of murine T cell lines, T cell clones, hybridomas and transfectomas." Methods in Microbiology (Academic Press, New York) 25 :.

[Publications] E. G. Rodrigues: "Single immunizing dose of recombinant adenovirus efficiently induces CD8^+T cell-mediated protective immunity against malaria." J. Immunol.158. 1268-1274 (1997)

[Publications] O. Igarashi: "IL-12R expression and accumulation of IL-12Rβ1 and IL-12Rβ2 mRNAs in CD4^+T cells by the costimulation with B7-2 molecules." J. Immunol.in press.

[Publications] T. Kato: "Diffeential effects of LPS and CD40 ligand stimulations on the induction of IL-12 production by dendritic cells and macrophages." Cell. Immunol.181. 59-67 (1997)

[Publications] T. Kato: "Costimulatory effect of IL-12 on the activation of naive, memory CD4+T cells, and Thl clone." Cell. Immunol.176. 50-58 (1997)

[Publications] M. Utsuyama: "Impairment of signal transduction in T cells from old mice." Mech. Ageing Develop.93. 131-144 (1997)

[Publications] H. Nakano: "A novel mutant gene involved in T lymphocyte specific homing into peripheral lymphoid organs on murine chromosome 4." Blood. (in press).

[Publications] R. Hakamada: "Expression and costimulatory function of B7-2 on murine CD4^+T cells." Eur. J. Immunol. (in press).

[Publications] S. Yamanouchi: "T cell activation antigen Ly6C induced on CD4^+Thl cells mediates an inhibitory signal for secretion of IL-2 and proliferation in peripheral immune responsse." Eur. J. Immunol.(in press).

善本隆之東京大学, 医科学研究所, 助手 (80202406)