Browsing by Author "Wayne A. Tompkins, Committee Co-Chair"

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    CD4+CD25+ Regulatory T Cells are Infected and Activated Phenotypically and Functionally During Acute Infection with Feline Immunodeficiency Virus.
    (2008-03-02) Mexas, Angela Marie; Gregg A. Dean, Committee Member; Linda Martin, Committee Member; Mary B. Tompkins, Committee Chair; Wayne A. Tompkins, Committee Co-Chair
    HIV-induced AIDS may be mediated by the activation of immunosuppressive CD4+CD25+ T regulatory cells (Tregs). Tregs have been shown to regulate CD4+ and CD8+ immune responses to HIV and FIV antigens in vitro. We tested the hypothesis that Tregs become infected and activated during the acute stage of FIV infection leading to the suppression of CD4+ T helper cell responses. Cats were experimentally infected with FIV-NCSU-1 and blood and lymph node biopsies were collected at 1 week intervals following inoculation. Real-Time PCR was used to determine plasma viremia and relative number of FIV copies in CD4+CD25+ and CD4+CD25- T cell subsets. Flow cytometry was used to assess the absolute numbers of each cell type and the expression of activation markers. Real-time RT-PCR was also used to assess relative increases in FoxP3 and TGF- mRNA levels over time. Treg suppression of IL-2 production in CD4+ T helper cells was assessed by ELISPOT assays and inhibition of cellular proliferation was assessed by incorporation of tritiated thymidine and CFSE. Our results show that peak viremia levels correlate with maximal infectivity in lymph node CD4+CD25+ populations. FIV-gag-mRNA levels are higher in CD4+CD25+ T cells than CD4+CD25- lymph node T cells. Activation of FoxP3 and increased expression of TGF1 in CD4+CD25+ cells correlates with peak plasma viremia and FIV-gag-mRNA levels in CD4+CD25+ T cells. Regulatory function can be detected in CD4+CD25+ T cells during the acute phase of FIV infection. Our findings support the hypothesis that early activation of immunosuppressor function in Treg cells may limit an effective anti-FIV response contributing to the establishment of the chronic infection and the immunodeficiency caused by this virus.
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    The Role of Complementary Proteins in Autoimmune Glomerulonephritis
    (2008-05-08) Pressler, Barrak; Wayne A. Tompkins, Committee Co-Chair; Shelly L. Vaden, Committee Co-Chair; Gloria A. Preston, Committee Member; Ronald J. Falk, Committee Member; Paul R. Hess, Committee Member
    Although numerous theories exist proposing mechanisms whereby autoimmune diseases may be initiated, as of yet none of these have been definitively shown to be responsible for the induction of any naturally-occurring disease. One of these theories, known as autoantigen complementarity, states that the initiator of an autoimmune response may not be the target autoantigen itself or an exogenous mimic, but instead is a peptide or protein that is 'antisense' or 'complementary' in shape and/or charge to the autoantigen. The first immune response is therefore production of an antibody specific for this complementary protein, followed by an anti-antibody (i.e. anti-idiotypic antibody) that reacts with the paratope of the first antibody and also recognizes the 'sense' or self-protein due to surface contour, charge, and⁄or hydropathy complementarity. Our laboratory group has published evidence for autoantigen complementarity in one autoimmune glomerular disease, proteinase-3 specific antineutrophil cytoplasmic autoantibody glomerulonephritis. The overall objective of the work described here was to provide further evidence for complementary proteins as inciting antigens in autoimmune glomerulonephritis using anti-GBM disease as the classic antibody-mediated autoimmune glomerulopathy; our central hypothesis was that anti-GBM disease is caused by a protein or peptide complementary to the anti-GBM autoantigen. The design of synthetic peptides complementary in sequence to portions of the human and rat α3(IV)NC1 collagen domains, and the design and production of a recombinant complementary α3(IV)NC1 protein more likely to possess appropriate tertiary structure to be complementary in sequence and in structure to the full-length anti-GBM epitope are described. These antigens were used to demonstrate that a subset of patients with anti-GBM disease have anti-idiotypic antibodies specific for α3(IV)NC1-complementary peptides and proteins, that these antibodies are distinct from their pathogenic idiotypic partners, and that the anti-GBM antibodies bind to these anti-complementary protein antibodies as expected by idiotypic:anti-idiotypic partners. Finally, we describe the immunologic and clinicopathologic consequences of immunization of two rodent models with anti-GBM-complementary peptides, thus providing provisional evidence for autoantigen complementarity-induced anti-GBM disease.