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Processing and Presentation of Glutamic Acid Decarboxylase 65 T cell-Inducing Epitopes: Implications in the Non-Obese Diabetic Mouse Model of Type 1 Diabetes

Rasche, Sarah S.

Abstract Details

2010, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
Type I Diabetes (T1D) is an autoimmune disease characterized by T cell-mediated inflammation of the pancreatic Islets of Langerhans, which results in beta (β) cell death and subsequent loss of insulin production. Ongoing human clinical trials suggest that targeting of autoreactive, β cell-specific T cells offers prospects for successful treatment of recent-onset T1D. The non-obese diabetic (NOD) mouse is an animal model of human T1D. T cell responses to glutamic acid decarboxylase 65kD (GAD65) are detectable in the spleens of prediabetic NOD mice and in the peripheral blood of prediabetic humans. T cells specific for GAD65 contribute to a diverse immune environment in the pancreas; responses to the immunogen can be either pathogenic or regulatory in nature. We have identified three carboxy terminal GAD65 determinants that yield either pathogenic cytotoxic T lymphocytes (CTL), T helper cells (Th1), or immunoregulatory T helper (Th2)-like T cell populations. GAD65 peptide 546-554 (p546)-specific CTL and GAD65 peptide 530-43 (p530)-specific Th1 are present in naïve NOD mice and are able to induce islet inflammation upon transfer into NOD severe combined immunodeficient (NOD.scid) recipients. GAD65 peptide 524-538 (p524)-specific Th2-like cells secrete IL-13 and suppress the activities of pathogenic Th1 cells. Since the three T cell-inducing epitopes are either proximal or overlapping in the GAD65 sequence, we wanted to investigate the processing mechanisms involved in epitope generation. We find that both macrophages and dendritic cells generate p546 from soluble, long GAD65 fragments by a TAP, ER, and proteasome-independent mechanism. While GAD65 p546 induces pathogenic CTL and GAD65 p530 induces proinflammatory Th1 cells, immunization with GAD65 p524-38 induces an immunoregulatory T cell population that protects NOD mice from T1D. p524-reactive T cells produce interleukin-13 (IL-13) that directly modulates IFN-γ production and proliferation of pathogenic GAD65 p530-5543 (p530)-specific T cells in NOD mice. Therefore, antigen processing and epitope selection may influence the balance dynamic between immune regulation and progressive autoimmune disease via the recruitment of specific T cell subsets.
Anthony Quinn, PhD (Advisor)
Deborah Vestal, PhD. (Committee Member)
Randall Worth, PhD. (Committee Member)
Hermann von Grafenstein, PhD. (Committee Member)
William Taylor, PhD. (Committee Member)
135 p.

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Citations

  • Rasche, S. S. (2010). Processing and Presentation of Glutamic Acid Decarboxylase 65 T cell-Inducing Epitopes: Implications in the Non-Obese Diabetic Mouse Model of Type 1 Diabetes [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290046839

    APA Style (7th edition)

  • Rasche, Sarah. Processing and Presentation of Glutamic Acid Decarboxylase 65 T cell-Inducing Epitopes: Implications in the Non-Obese Diabetic Mouse Model of Type 1 Diabetes. 2010. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290046839.

    MLA Style (8th edition)

  • Rasche, Sarah. "Processing and Presentation of Glutamic Acid Decarboxylase 65 T cell-Inducing Epitopes: Implications in the Non-Obese Diabetic Mouse Model of Type 1 Diabetes." Doctoral dissertation, University of Toledo, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290046839

    Chicago Manual of Style (17th edition)