1998 Fiscal Year Final Research Report Summary
Therapeutic trial for allergic disorders and infectious disease with IL-18.
| Project/Area Number |
09557031
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Immunology
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| Research Institution | Hyogo College of Medicine |
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Principal Investigator |
NAKANISHI Kenji Hyogo College of Medicine, Department of Immunology and Medical Zoology, Professor, 医学部, 教授 (60172350)
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| Co-Investigator(Kenkyū-buntansha) |
AKIRA Shizuo Hyogo College of Medicine, Department of Biochemistry, 医学部, 教授 (50192919)
OKAMURA Haruki Hyogo College of Medicine, Institute for Advanced Medical Sciences, 医学部, 助教授 (60111043)
YOSHIMOTO Tomohiro Hyogo College of Medicine, Department of Immunology and Medical Zoology, Associa, 医学部, 助教授 (60241171)
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| Project Period (FY) |
1997 – 1998
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| Keywords | IL-18 / IL-18R / anti-allergic action / Th1 cells / IFN-gamma / modulation of host immunity / L.major |
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| Research Abstract |
IL-18 is a pleiotropic cytokine. We investigated the action of H-18 on IgE response and host immunity. As T and B cells require co-stimulation with IL-12 to respond to IL-18 by striking IFN-gamma production, we investigated expression of IL-18R on T and B cells. We found IL-12-stimulated T and B cells express both high and low affinity IL-18R.We also investigated the mechanism how IL-18 induces IFN-gamma production from Th1 cells but not from Th2 cells. We revealed that only Th1 cells express both high and low affinity (J.Immunol., 1998). Administration of IL-18 and IL-12 strikingly induces T, B and NK cells to produce IFN-gamma that inhibits IL-4-dependent polyclonal IgE production in helminth-infected mice (PNAS, 1997). We revealed that administration of IL-12 also induces IL-18R on T and B cells in vivo. Thus, IL-18 when administered with IL-12 can effectively induces T and B cells to produce IFN-GAMMA.Thus, IL-12 and IL-18 inhibit IgE production in vivo by shifting the balance of Th1 and Th2 toward Th1 dominance. We also investigated the mechanism how IgE production is inhibited in SJL mice. We could reveal that IL-18 and IL-12 from LPS-stimulated macrophages synergistically induce unique T cells (CD4-CD8-double negative CD3^<int>IL-2Rbeta T cells) to secrete IFN-gamma and to express FasL, which in combination inhibits IgB production from B cells (J.Immunol., 1998).
Since IL- 12 and IL-18 synergize for IFN-gamma production from T and B cells, we investigated whether administration of IL-12 and IL-18 could present a unique approach for the treatment of L.major susceptible BALB/c mice. We could reveal this combination induces Th1 cells that protect mice from L.major infection-induced footpad swelling. Moreover, these treated mice showed strong resistance against reinfection with L.major.
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