Role of Th1 Immune Responses in the Pathogenesis of Hypertensive Kidney Injury

Th1 免疫反应在高血压肾损伤发病机制中的作用

• 批准号: 8707438
• 负责人: Steven D Crowley
• 金额: $ 32.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2016-04-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707438
• 关键词: Address; Affect; Angiotensin II; Animals; Antibody Formation; Antigen-Presenting Cells; Attenuated; Blood Pressure; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Lineage; Cells; Characteristics; Chronic; Chronic Kidney Failure; Clinical Trials; Complex; Critical Pathways; Cytokine Network Pathway; Development; Generations; Genetic; Genetic Drift; Genetic Programming; Helper-Inducer T-Lymphocyte; Hypertension; Immune; Immune response; Immune system; Immunosuppressive Agents; Individual; Infiltration; Inflammation Mediators; Inflammatory; Infusion procedures; Injury; Injury to Kidney; Interferons; Kidney; Kidney Diseases; Laboratories; Lead; Macrophage Activation; Mediating; Modeling; Modification; Mus; Nature; Organ; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Production; Proteinuria; Receptor, Angiotensin, Type 1; Relative (related person); Renin-Angiotensin System; Role; Source; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Techniques; Testing; Th1 Cells; Th2 Cells; Tissues; Transplantation; Tumor Necrosis Factor-alpha; Viral Tumor Antigens; Wild Type Mouse; cytokine; cytotoxic; design; inhibitor/antagonist; macrophage; prevent; public health relevance; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) plays a key role in the pathogenesis of chronic kidney injury. Clinical trials with RAS inhibitors suggest angiotensin II (Ang II) may promote renal injury through blood pressure- independent effects. Activation of the immune system by the RAS has been suggested as one mechanism mediating these actions. We have found that chronic infusion of Ang II causes significant kidney injury, infiltration of CD4+ T helper lymphocytes into the kidney, and enhanced expression of pro-inflammatory cytokines including interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a). Administration of the broadly acting immunosuppressive agent mycyophenolate mofetil (MMF) abrogated these effects without affecting blood pressure. Accordingly, we hypothesize that activation of a CD4+ T cell-dependent cellular immune response by Ang II contributes to chronic kidney damage in this setting. Typically, CD4+ T cells do not directly mediate cytotoxic tissue injury. Rather, they regulate immune responses by differentiating into type 1 (Th1) or type 2 (Th2) CD4+ T helper cells. Whereas Th2 cells regulate antibody responses, Th1 cells secrete IFN-g leading to activation of macrophages and cytotoxic CD8+ T cells to mediate cellular damage. Activated macrophages in turn produce TNF-a, which further stimulates Th1 cells. We therefore suggest that Ang II acting through type I angiotensin (AT1) receptors promotes the development of a Th1 immune response in the kidney, with enhanced production of IFN-g and TNF-a leading directly to progressive kidney disease through blood pressure-independent mechanisms. To test this, we will examine Ang II-induced kidney injury in mouse lines with genetic modifications impacting: transcription factors critical for Th1 differentiation, key Th1 cytokines, and AT1 receptor responses in key cell lineages. In addition to CD4+ T cells, IFN-g and TNF-a are expressed by several immune cell lineages and even by renal parenchymal cells. Therefore, we have designed experiments to identify the cellular sources of these cytokines in Ang II- dependent kidney injury. Understanding how Th1 immune responses influence Ang II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease.

描述（申请人提供）：肾素-血管紧张素系统（RAS）在慢性肾损伤的发病机制中发挥着关键作用。 RAS 抑制剂的临床试验表明，血管紧张素 II (Ang II) 可能通过与血压无关的作用促进肾损伤。 RAS 激活免疫系统被认为是介导这些作用的一种机制。我们发现，长期输注Ang II会导致严重的肾损伤，CD4+ T辅助淋巴细胞浸润到肾脏，并增强促炎细胞因子的表达，包括干扰素-g (IFN-g) 和肿瘤坏死因子-a (TNF-a)。给予广泛作用的免疫抑制剂霉酚酸酯（MMF）可以消除这些影响而不影响血压。因此，我们假设 Ang II 激活 CD4+ T 细胞依赖性细胞免疫反应会导致这种情况下的慢性肾损伤。通常，CD4+ T 细胞不直接介导细胞毒性组织损伤。相反，它们通过分化为 1 型 (Th1) 或 2 型 (Th2) CD4+ T 辅助细胞来调节免疫反应。 Th2 细胞调节抗体反应，而 Th1 细胞分泌 IFN-g，导致巨噬细胞和细胞毒性 CD8+ T 细胞激活，介导细胞损伤。激活的巨噬细胞反过来产生 TNF-a，进一步刺激 Th1 细胞。因此，我们认为，Ang II 通过 I 型血管紧张素 (AT1) 受体发挥作用，促进肾脏中 Th1 免疫反应的发展，同时增加 IFN-g 和 TNF-a 的产生，通过与血压无关的机制直接导致进行性肾脏疾病。为了测试这一点，我们将检查 Ang II 诱导的小鼠系肾损伤，其基因修饰影响：对 Th1 分化至关重要的转录因子、关键 Th1 细胞因子和关键细胞谱系中的 AT1 受体反应。除了 CD4+ T 细胞外，几种免疫细胞谱系甚至肾实质细胞也表达 IFN-g 和 TNF-a。因此，我们设计了实验来鉴定 Ang II 依赖性肾损伤中这些细胞因子的细胞来源。了解 Th1 免疫反应如何影响 Ang II 诱导的肾损伤应该有助于制定更有效的策略来预防进行性慢性肾病。