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Therapeutic trial for allergic disorders and infectious disease with IL-18.

IL-18 治疗过敏性疾病和传染病的试验。

基本信息

批准号：
09557031
负责人：
NAKANISHI Kenji
金额：
$ 1.73万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557031/
关键词：
IL-18 IL-18R anti-allergic action Th1 cells IFN-gamma modulation of host immunity L.major

项目摘要

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.

IL-18是一种多效性细胞因子。我们研究了H-18对IgE反应和宿主免疫的作用。由于T和B细胞需要IL-12的共刺激以通过打击IFN-γ产生来响应IL-18，我们研究了IL-18 R在T和B细胞上的表达。我们发现IL-12刺激T细胞和B细胞表达高亲和力和低亲和力的IL-18 R，并研究了IL-18诱导Th 1细胞产生IFN-γ而不诱导Th 2细胞产生IFN-γ的机制。我们揭示了只有Th 1细胞表达高和低亲和力（J.Immunol.，1998年）。施用IL-18和IL-12显著诱导T、B和NK细胞产生IFN-γ，其抑制蠕虫感染小鼠中IL-4依赖性多克隆IgE的产生（PNAS，1997）。我们揭示了IL-12的施用也在体内诱导T和B细胞上的IL-18 R。因此，当IL-18与IL-12一起施用时，IL-18可以有效地诱导T和B细胞产生IFN-γ。我们还研究了SJL小鼠中IgE产生被抑制的机制。我们可以揭示，来自LPS刺激的巨噬细胞的IL-18和IL-12协同诱导独特的T细胞（CD 4-CD 8-双阴性CD 3-<int>IL-2 R β T细胞）分泌IFN-γ并表达FasL，其组合抑制来自B细胞的Ig B产生（J.Immunol.，1998).由于IL- 12和IL-18协同从T和B细胞产生IFN-γ，因此我们研究了IL-12和IL-18的施用是否可以提供用于治疗大型李氏杆菌易感性BALB/c小鼠的独特方法。我们可以揭示这种组合诱导Th 1细胞，保护小鼠免受L.major感染诱导的足垫肿胀。此外，这些治疗的小鼠表现出较强的抵抗力，对再感染与L.主要。