Medicine (St Vincent's) - Theses
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ItemNew approaches to induce tolerance in autoantigen-specific memory T cells in type 1 diabetes( 2018)Autoimmune disorders like type 1 diabetes (T1D) result from the failure of immune tolerance mechanisms. Antigen-specific therapy constitutes an attractive approach to re-establish a tolerant state but has so far not been successful in clinical settings. Importantly, treatment after the onset of autoimmunity is likely to be less effective due to established autoimmune responses and active inflammation in the islets. Moreover, a major hurdle might be the persistence of antigen-experienced islet-reactive T cells and the induction of tolerance in these memory cells is challenging. Hence, therapies intended to induce antigen-specific tolerance may need additional immunomodulatory treatments to be effective in individuals with established autoimmunity. Here, we aimed to identify a combination of interventions that induces tolerance in antigen-specific memory T cells. For this study, we generated non-obese diabetic (NOD) mice with tetracycline-regulated expression of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) in antigen presenting cells (TII mice) and tracked IGRP-specific CD8+ T cells using tetramer enrichment. Notably, while naïve IGRP-specific T cells are eliminated upon antigen expression, memory T cells are refractory to cell depletion. Interestingly, these memory T cells up-regulated several exhaustion markers in response to antigen exposure but showed no functional impairment. We hypothesized that combining short-term treatment with non-Fc-binding anti-CD3 F(ab’)2 and the co-stimulation blocker abatacept together with antigen expression might induce effective tolerance in TII mice. However, after initial depletion of antigen-experienced IGRP-specific cells by anti-CD3 F(ab’)2, these cells re-expanded and were still functional. Thus, our combination approach has only limited efficacy in established autoimmunity. Combination therapies of antigen-specific therapies with agents that support the induction of complete T cell exhaustion might be more successful and should be tested in future studies.