Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by the T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans. For T1D patients, life-long insulin injections are necessary to help maintain normoglycemia, although constant blood glucose fluctuations lead to a variety of complications. Currently, the only way to "cure" T1D is with islet or pancreas transplantation. The aims of the studies described herein are to: (i) test the hypothesis that immunomodulating therapies targeting T cells will be able to prevent recurrent autoimmunity, and (ii) to understand the kinetics and specificities of the pathogenic T cells involved in recurrent autoimmunity.
Results from our first study in the non-obese diabetic (NOD) mouse model show that non-depleting anti- (α)CD4 and αCD8 coreceptor antibodies extend survival of syngeneic islet grafts in diabetic recipients. We also determined that via adeno-associated virus (AAV) vector gene delivery, ectopic expression of IL-2 by β cells also extended protection of syngeneic islet grafts. Surprisingly, the combination of αCD4 and αCD8 coreceptor antibodies with AAV vector mediated gene transfer of IL-2 did not extend islet graft protection over αCD4 and αCD8 treatment alone. Taken together, our results show that these two treatments do not act synergistically, although individually these immunotherapies extend islet graft survival. Our second study examined the T cell receptor (TCR) variable (V)β repertoire in islet grafts. In islet grafts of diabetic NOD recipients the effector/memory (eff/mem) CD8+ T cell repertoire in the islet graft showed decreased entropy, and is dominated by one to four TCR Vβ chains which varied markedly by mouse. The eff/mem CD4+ T cell repertoire in the islet graft was more diverse, though all NOD recipients showed an increase in frequency of TCR Vβ12-bearing T cells. Additionally, the eff/mem TCR repertoire of T cells infiltrating the islet graft was more similar to the pancreas repertoire than the TCR repertoires found in the draining renal lymph node, pancreatic lymph node, or spleen. This suggests that, in individual NOD recipients, the same specificies of effector/memory T cells may be involved in both initial and recurrent autoimmunity.
|Advisor:||Tisch, Roland M.|
|Commitee:||Clarke, Steven, Maile, Robert, Serody, Jonathan, Su, Maureen|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Microbiology & Immunology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 73/09(E), Dissertation Abstracts International|
|Keywords:||Diabetes, Immunotherapy, T cell receptors|
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