Aberrant T Cell Function and Immunopathogenesis of CMV Immune Recovery Uveitis

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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.