Aberrant T Cell Function and Immunopathogenesis of CMV Immune Recovery Uveitis

描述（由申请人提供）：在艾滋病和巨细胞病毒视网膜炎（CMVR）患者中，通过抗逆转录病毒治疗获得免疫恢复，并且可以停止抗巨细胞病毒治疗而没有进一步视网膜炎进展的患者中，出现了一种新的视力损害原因-免疫恢复性葡萄膜炎（IRU）。本研究的目的是探讨异常T细胞功能在CMV IRU免疫发病机制中的作用。我们建议用自身免疫和感染后葡萄膜炎的动物模型来检验以下假设，这些假设是由我们的初步数据和最近的报道提出的：1) CMV特异性CD4+和CD8+ T细胞因子反应的不平衡和/或调节性CD4+ T细胞（Treg）的缺陷在CMV IRU患者的PBMC中比在未发生IRU的免疫恢复CMVR患者中更常见；2)通过流式细胞术测量这种异常的T细胞反应可能具有潜在的临床应用价值，可用于筛选有发生IRU风险的免疫恢复CMVR患者。本建议采用病例对照设计。储存在nei赞助的CMVR自然历史的多中心观察性研究中收集的PBMC将被解冻，并通过流式细胞术检测cmv特异性CD4+ T细胞IL-2和CD8+ T细胞IFN？TNFa和CD107a/b反应及Treg含量。检测结果将比较病例和匹配的对照组，这些对照组均被诊断为艾滋病和CMVR，并通过抗逆转录病毒治疗获得免疫恢复，并且在父母纵向研究期间诊断为IRU（病例）或未诊断为IRU（对照组）。从PBMC中去除Treg和将回流分类的Treg细胞添加到Treg缺失的PBMC样本中对cmv特异性以及抗cd3诱导的CD8+ T细胞功能反应的影响也将被检查，以了解Treg功能可能影响cmv特异性CD8+ T细胞效应反应的机制。在这些后一种实验中，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依赖于这些细胞因子。巨细胞病毒视网膜炎（CMVR）在美国和欧洲仍然是艾滋病的一个重要并发症，并且在国际上，特别是在亚洲，正在成为一个重要的艾滋病并发症。在美国，巨细胞病毒免疫恢复性葡萄膜炎（IRU）目前占长期CMVR和抗逆转录病毒治疗介导的免疫恢复的艾滋病患者视力丧失事件的50%。巨细胞病毒感染没有有效的治疗方法。因此，了解CMV IRU的发病机制有助于开发有效的CMV IRU治疗方法或预防CMV IRU的诊断或治疗策略。

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.