MOUSE HEPATITIS VIRUS-ASSOCIATED IMMUNE DYSFUNCTION

小鼠肝炎病毒(MHV)感染高发的实验鼠 流行率和对许多生物医学学科的重大影响 都是常用的。淋巴细胞捐献者感染MHV导致T细胞 体外增殖和细胞因子所反映的细胞功能障碍 制作。然而，细胞因子在MHV发病机制中的作用 通过自然途径暴露小鼠后的感染尚未得到解决。 一旦这些分子的作用被牢固地确立，努力将 使鉴定分泌细胞因子的细胞类型(S)和细胞 类型(S)，他们将按照该类型进行操作。长期目标是发展 我省地方性MHV的合理防控策略 实验室里的小鼠群体。 拟议研究的具体目标是：1.进一步描述 细胞因子在MHV发病机制中的作用 诱导方法和细胞因子缺失；2.鉴定细胞类型 产生有益的细胞因子以及由这些细胞激活的那些 可溶的调解物。 当前提案的目标是检验以下假设 活化的T细胞和其他细胞释放的某些细胞因子 类型，可能介导感染MHV的良性结果。干扰素伽马 和白介素4是人们最感兴趣的分子。试点数据 提示CD4+T细胞的效应功能可能与 MHV感染的病理和阴性结果。T的这两个方面 细胞生物学很难分离；然而，药物和/或 抗体诱导的细胞缺失结合细胞因子免疫治疗将 开始暗示我们的假设是否有道理。是否可以使用 基因定义的小鼠、重组细胞因子、单抗 与这些分子和细胞特异性药物的反应提供了一种方法 对体内病毒与免疫系统的相互作用是可行的。

Mouse hepatitis virus (MHV) infection of laboratory mice occurs at high prevalence and impacts heavily on many biomedical disciplines in which mice are commonly used. Infection of lymphocyte donors with MHV results in T cell dysfunction, as reflected by in vitro proliferation and cytokine production. However, the role of cytokines in the pathogenesis of MHV infection after exposure of mice by natural routes has not been addressed. Once the role of these molecules has been firmly established, efforts will be made to identify the cell type(s) secreting cytokines and the cell type(s) upon which they act. The long-term goal is the development of rational strategies for control and prevention of enzootic MHV in laboratory mouse colonies. The specific aims of the proposed research are: 1. to characterize further the role of cytokines in MHV pathogenesis, using cytokine immunotherapy or induction methods and cytokine deletion, and 2. to identify the cell types producing beneficial cytokines as well as those that are activated by these soluble mediators. The objective of the current proposal is to test the hypothesis that certain cytokines released by activated T cells, as well as other cell types, may mediate benign outcome of infection with MHV. Interferon gamma and interleukin 4 are the molecules of primary interest. Pilot data suggest that effector function of CD4+ T cells may be associated with pathology and negative outcome of MHV infection. These two aspects of T cell biology are difficult to separate; however, drug- and/or antibody-induced cell deletion combined with cytokine immunotherapy will begin to suggest whether our hypothesis has merit. The availability of genetically defined mice, recombinant cytokines, monoclonal antibodies reactive with these molecules and cell-specific drugs renders an approach to the in vivo interactions of virus and the immune system feasible.