Exploiting antigen specific approaches to induce tolerance in Type 1 Diabetes

Abstract

Given the prevalence of MHC-class II-restricted T cell responses in driving autoimmune disease, it is not surprising that numerous therapeutic strategies have been designed to target CD4+ T cells in the hope of attenuating autoimmunity and restoring self-tolerance. Our lab has previously demonstrated that the intravenous administration of antigen-pulsed, ethylenecarbidiimide-fixed splenic antigen-presenting cells can promote long-lived clonal anergy of antigen-specific CD4+ T cells both in vitro and in vivo. In this study, we used the NOD.BDC2.5.Thy1.1 CD4+ transgenic mouse model of Type I Diabetes as a reductionist approach to understand how these antigen-coupled cells induce peripheral tolerance. Though administration of antigen-coupled cells is a powerful method of tolerance induction, antigen-coupled cell therapy is not optimal. This is in part because the mechanism(s) of antigen-coupled cell induced tolerance have yet to be elucidated. Though the route of administration, dosage, levels of costimulation, T cell polarization and regulatory T cell induction are all likely to contribute to tolerance induction by antigen-coupled cells, their relative contributions have yet to be defined. The goal of this thesis is to understand the mechanisms underlying the processing and presentation of antigen-coupled cells, with the ultimate goal of using that information to improve the efficacy of this therapeutic.