C3aR and C5aR Modulate T-cell Responses in the MRL Mouse

C3aR 和 C5aR 调节 MRL 小鼠的 T 细胞反应

• 批准号: 7031858
• 负责人: MICHAEL C BRAUN
• 金额: $ 28.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031858
• 关键词: anaphylatoxins; antigen presentation; apoptosis; cell proliferation; cell surface receptors; disease /disorder model; extracellular matrix; immune response; kidney pharmacology; kidney transplantation; laboratory mouse; lupus nephritis; lymphocyte; model design /development; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is a heterogeneous disorder characterized by autoimmunity and the development of progressive immune complex renal disease. The pathogenesis of SLE is complex and multi- factorial; substantial clinical and experimental data supports roles for auto-antibodies, immune complexes, apoptosis, and effector T-cells in the development of SLE. Disturbances in the complement system are strongly associated with the development and progression of many forms of SLE particularly lupus nephrits. Complement activation results in the production of anaphylatoxins, C3a and C5a, which signal through ubiquitously expressed G-protein coupled receptors (C3aR and C5aR). Signaling via the C3aR and C5aR has historically thought to function to active innate immune responses. The studies contained in this proposal are designed to define and characterize the ability of C3aR and C5aR to alter adaptive immune responses in a biologically relevant complement dependent model of human disease, namely the MRL/lpr mouse model of lupus nephritis. Mice with targeted deletions of C3aR and C5aR as well as mice deficient in both the C3aR and the C5aR have been back-crossed 9 generations on to the MRL/lpr genetic background. Comparative studies of renal injury and immunologic responses including antigent presenting cell function, T-cell, and B-cell function will be performed. Additionally, experiments investigating renal parenchymal responses in terms of cellular proliferation, extra-cellular matrix production, and apoptosis will be performed. These studies are designed to advance our understanding of the mechanisms by which complement activation products modulate cellular immune responses and renal parenchymal responses in immune mediated renal injury.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种异质性疾病，其特征是自身免疫和进行性免疫复合物肾病的发展。SLE的发病机制是复杂和多因素的;大量的临床和实验数据支持自身抗体、免疫复合物、细胞凋亡和效应T细胞在SLE发展中的作用。补体系统的紊乱与许多形式的SLE特别是狼疮性肾炎的发生和进展密切相关。补体激活导致过敏毒素C3 a和C5 a的产生，其通过普遍表达的G蛋白偶联受体（C3 aR和C5 aR）发出信号。通过C3 aR和C5 aR的信号传导在历史上被认为对主动先天免疫应答起作用。本提案中包含的研究旨在定义和表征C3 aR和C5 aR改变人类疾病的生物学相关补体依赖性模型（即狼疮肾炎的MRL/lpr小鼠模型）中适应性免疫应答的能力。具有C3 aR和C5 aR靶向缺失的小鼠以及C3 aR和C5 aR两者缺陷的小鼠已经在MRL/lpr遗传背景上回交9代。将进行肾损伤和免疫应答的比较研究，包括抗原呈递细胞功能、T细胞和B细胞功能。此外，还将进行实验，研究肾实质在细胞增殖、细胞外基质产生和细胞凋亡方面的反应。这些研究旨在促进我们对补体激活产物调节免疫介导的肾损伤中的细胞免疫应答和肾实质应答的机制的理解。