FCR DEFICIENT MICE SUSCEPTIBILITY TO PATHOGENS

FCR 缺陷小鼠对病原体的易感性

• 批准号: 6627996
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 29.62万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627996
• 关键词: B lymphocyte; Cryptococcus neoformans; Schistosoma mansoni; T lymphocyte; antibody receptor; antigen antibody reaction; antireceptor antibody; biological signal transduction; cellular immunity; complement pathway; delayed hypersensitivity; gene targeting; host organism interaction; humoral immunity; immunoglobulin G; laboratory mouse; life cycle; macrophage; mast cell; microorganism immunology; parasitic diseases; receptor binding; skin hypersensitivity

Knowledge of the relative contributions of innate and adaptive immunity in host resistance to pathogens is essential both to an understanding the basic immunological mechanisms involved and in the design of effective immunotherapies. We have employed targeted gene disruption approaches to define the role of specific components of the antibody- effector cell pathway in host susceptibility to the encapsulated fungus Cryptococcus neoformans and the trematode Shistosoma mansoni. Mouse strains deficient in the activation subunit of Fc receptors, FcRgamma, have significant defects in type I, II and III inflammation, and manifest specific alterations in their responses to these pathogens. In C. neoformans the role of IgG/FcgammaR interactions has been studied in a model of passive immunotherapy employing IgG switch variants of an anti-capsular GXM antibody. Thus, IgG1 antibodies are protective and require the expression of FcRgamma chain while IgG3 antibodies enhance infection in both FcRgamma-/- and wild-type strains, implying the existence of a novel IgG3 FcR. We will pursue these observations to determine 1) The contribution of individual FcRs on specific effector cells to the sub-class differences in protection, 2) The structure of the IgG3 FcR and its relationship to the known FcRs and 3) The signal transduction pathways triggered by IgG3 binding to its FcR. In S. mansoni infection, pathology results from sensitized CD4 cells triggering granuloma formation, fibrosis and subsequent circulatory impairment. B cell deficient animals or animals lacking FcRgamma show enhanced tissue responses to egg deposition. Egg granulomas are larger and fail to undergo down-modulation during the chronic phase of infection in both deficient strains. These studies suggest a novel and previously unappreciated role for antibody-FcR interactions in modulating T cell mediated reactions. In addition, B cell deficient mice are impaired in their ability to excrete eggs, independently of FcRgamma expression. We propose to extend on these results by 4) Characterizing the specific FcRs and effector cells responsible for the enhanced granuloma response, 5) Determining the antibody receptors responsible for egg excretion and 6) Investigating the generality of antibody-FcR interactions as modulators of T cell responses by characterizing contact sensitivity and DTH reactions in FcR deficient animals.

了解先天和适应性免疫的相对贡献 在宿主对病原体的抵抗中，对理解至关重要 涉及的基本免疫机制和设计 有效的免疫疗法。 我们采用了靶向基因破坏 定义抗体特定成分的作用的方法 宿主对封装真菌易感性的效应细胞途径 加密赛车菌和Trematode shistosoma Mansoni。 老鼠 FC受体FCRGAMMA的激活亚基的菌株不足 I型，II和III炎症有明显的缺陷，并且 在其对这些病原体的反应中表现出特定的改变。 在Neoformans中 在采用IgG开关变体的被动免疫疗法模型中 抗囊型GXM抗体。因此，IgG1抗体具有保护性和 需要表达fcrgamma链，而IgG3抗体增强 fcrgamma - / - 和野生型菌株中的感染，这意味着 新颖的IgG3 FCR的存在。 我们将追求这些观察 确定1）单个FCR对特定效应器的贡献 细胞与保护的子类别差异，2） IgG3 FCR及其与已知FCR的关系，3）信号 由IgG3与其FCR结合触发的转导途径。 在S. Mansoni感染，病理学来自致敏的CD4细胞 触发肉芽瘤形成，纤维化和随后的循环系统 损害。 B细胞不足的动物或缺乏FCRGAMMA的动物显示 增强组织对卵子沉积的反应。 卵肉芽瘤更大 并且在慢性阶段未能进行下调 两种不足菌株的感染。 这些研究表明了一本小说， 以前在抗体-FCR相互作用中未接受的作用 调节T细胞介导的反应。 另外，B细胞不足 小鼠的排泄卵能力受损，独立于 fcrgamma表达。 我们建议将这些结果扩展到4） 表征负责的特定FCR和效应细胞 增强的肉芽瘤反应，5）确定抗体受体 负责鸡蛋排泄和6）调查一般性 抗体-FCR相互作用作为T细胞反应的调节剂 表征FCR缺乏的接触灵敏度和DTH反应 动物。