Aberrant T Cell Function and Immunopathogenesis of CMV Immune Recovery Uveitis

T 细胞功能异常与巨细胞病毒免疫恢复性葡萄膜炎的免疫发病机制

• 批准号: 7336264
• 负责人: MARK A JACOBSON
• 金额: $ 23.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336264
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Animal Model; Anti-Retroviral Agents; Antibodies; Antigens; Asia; Autoimmune Process; Back; Biological Assay; Blindness; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical; Color; Complication; Country; Cytomegalovirus; Cytomegalovirus Retinitis; Cytotoxic T-Lymphocytes; Data; Development; Diagnosis; Diagnostic; Disease; Enrollment; Equilibrium; Europe; Eye; Flow Cytometry; Frequencies; Homeostasis; IL2RA gene; Immune; Incidence; Inflammation; Interferon Type II; Interferons; Interleukin 2 Receptor; Interleukin-2; Light; Longitudinal Studies; Measurement; Measures; Mediating; Monoclonal Antibody HuM291; Muromonab-CD3; Natural History; Necrosis; Numbers; Observational Study; Parents; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Publications; Recovery; Regulation; Relative (related person); Reporting; Resources; Retinal; Retinal Detachment; Retinitis; Risk; Role; Screening procedure; Sorting - Cell Movement; Specimen; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Treatment Protocols; Uveitis; Visit; Visual impairment; antiretroviral therapy; case control; cytokine; cytotoxic; design; follow-up; indexing; macular edema; prevent; research study; response

DESCRIPTION (provided by applicant): Among patients with AIDS and cytomegalovirus retinitis (CMVR) who have become immunorestored by antiretroviral therapy and can discontinue anti-CMV therapy without further retinitis progression, a new cause of visual impairment has emerged-- immune recovery uveitis (IRU). The aim of this proposal is to investigate the role that aberrant T cell function may have in the immunopathogenesis of CMV IRU. We propose to test the following hypotheses, which are suggested by our preliminary data and by recent reports with animal models of autoimmune and post-infectious uveitis: 1) that an imbalance between CMV-specific CD4+ and CD8+ T cell cytokine responses and/or a deficit in regulatory CD4+ T cells (Treg) are more common in PBMC of patients with CMV IRU than in immunorestored CMVR patients who do not develop IRU and 2) that measuring such aberrant T cell responses by flow cytometry may have potential clinical utility as a screening test to identify immunorestored CMVR patients at risk for developing IRU. This proposal has a case-control design. Stored PBMC that have already been collected in an NEI-sponsored, multicenter, observational study of CMVR natural history will be thawed and assayed by flow cytometry for CMV-specific CD4+ T cell IL-2 and CD8+ T cell IFN?, TNFa and CD107a/b responses and Treg content. Assay results will be compared from case and matched controls who were all diagnosed with AIDS and CMVR and were immunorestored by antiretroviral therapy and who did (cases) or did not (controls) have IRU diagnosed during the parent longitudinal study. The effect of depleting Treg from PBMC and of adding back flow-sorted Treg cells to Treg-depleted PBMC specimens on CMV-specific, as well as anti-CD3-induced, CD8+ T cell functional responses will also be examined in order to understand the mechanism by which Treg function may impact on CMV-specific CD8+ T cell effector responses in cases and controls. In these latter experiments, anti-IL-10 and/or anti-TGF¿ antibodies will also be used to test whether regulation of CMV-specific CD8+ T cell responses depends on these cytokines. Cytomegalovirus retinitis (CMVR) remains an important complication of AIDS in the US and Europe and is emerging as an important AIDS complication internationally, especially in Asia. In the US, CMV immune recovery uveitis (IRU) now accounts for 50% of incident vision loss in AIDS patients with longstanding CMVR and antiretroviral treatment-mediated immune recovery. There is no effective therapy for CMV IRU. Thus, understanding the disease mechanism of CMV IRU could facilitate development of effective therapy for CMV IRU or diagnostic or treatment strategies to prevent CMV IRU.

描述（由适用提供）：在患有抗逆转录病毒疗法免疫修养的艾滋病和巨细胞病毒视网膜炎患者中，可以停止抗CMV疗法，而没有进一步的视网膜炎，而没有进一步的视觉障碍，新的视觉障碍原因已经出现了 - 免疫发现静脉内炎（IRU）。该提案的目的是研究异常T细胞功能在CMV IRU的免疫发作中可能具有的作用。我们建议测试以下假设，这些假设由我们的初步数据以及最近的自身免疫性和感染后葡萄膜炎的动物模型提出的建议：1）CMV特异性CD4+和CD8+ T细胞细胞因子反应和/或在PBM中的防御性CD4+ T细胞中的不平衡（TREG）在CMC中的不平衡（TREG）更为常见。不开发IRU的CMVR患者和2）通过流式细胞仪测量这种异常T细胞反应的患者可能具有潜在的临床实用性作为筛查测试，以鉴定有生长IRU风险的免疫保存的CMVR患者。该提案具有案例对照设计。已经在CMVR自然史的Nei赞助的，多中心的观察性研究中收集的储存的PBMC将被流式细胞仪解冻和分配，用于CMV特异性CD4+ T细胞IL-2和CD8+ T细胞IFN？，TNFA和CD107A/B响应和Treg含量和Treg含量。分析结果将与均被诊断为AIDS和CMVR的病例和匹配的对照组进行比较，并通过抗逆转录病毒疗法进行免疫培养，并且在父母纵向研究期间（病例）或没有（病例）或没有（对照组）具有IRU诊断。从PBMC中耗尽的TREG和将背部流动的Treg细胞添加到Treg缺失的PBMC规范对CMV特异性以及抗CD3诱导的抗CD8+ T细胞功能响应的影响，还将检查TREG功能对CMV-sperific cys cys and cys and treg的效果，以了解CD8+ T细胞效应，以了解TREG的功能。在这些后来的实验中，抗IL-10和/或抗TGF¿抗体也将用于测试CMV特异性CD8+ T细胞反应的调节是否取决于这些细胞因子。巨细胞病毒视网膜炎（CMVR）仍然是美国和欧洲的艾滋病的重要并发症，并且正在成为国际上的重要辅助并发症，尤其是在亚洲。在美国，CMV免疫恢复葡萄膜炎（IRU）现在占长期CMVR和抗逆转录病毒治疗介导的免疫记录的AIDS患者的事件视力丧失的50％。 CMV IRU没有有效的疗法。这就是了解CMV IRU的疾病机制，可以促进开发有效的CMV IRU或诊断或治疗策略，以防止CMV IRU。