Regeneration of insulin-producing [beta]-cells during recovery from disease: a cure for Type 1 Diabetes
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type 1 diabetes (T1D) is a chronic disease condition characterized by destruction of the insulin-producing [beta]-cells by self-reactive lymphocytes of the immune system. While some immunotherapeutic approaches against T1D directly target and modulate diabetogenic specific T cells or the entire T cell repertoire, other efforts utilize antigen presenting cells or T cell-regulating molecules to control the T cells. In chapter II, we set out to determine the role of regulatory cytokines, IL-4 and IL-13 in T1D progression. IL-4 and IL-13 are widely reported as anti-inflammatory cytokines, and both can signal via the IL-4R[alpha]/IL-13R[alpha]1 heteroreceptor (HR). To determine the role of these cytokines in T1D development, we generated NOD mice in which the IL-13R[alpha]1 arm of the HR is deleted, thereby rendering the HR nonfunctional. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level (BGL) and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This outcome is likely due to an increase in the frequency of mTGF[beta][subscript +]Foxp3[subscript int] regulatory T cells and persistence of CD206[subscript +] macrophage in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D. In chapter III, we investigate the source of newly formed β-cells during recovery from overt T1D under a combination therapy that involves an immunoglobulin chimera, Ig-GAD2 and bone marrow cells transfer. This combination therapy proved effective in driving immune modulation of diabetogenic-specific T cells and repair of the islet vasculature leading to the formation of new endogenous [beta]-cells that were able to thrive and restore long-lasting normoglycemia. Our new findings reveal and suggest that the combination therapy leads to the formation of healthy islets by inducing division of residual β-cells and differentiation of precursor cells. Furthermore, while the pancreas is cleared of immune infiltration during recovery from disease, both the lymph nodes and spleen displayed a significant reduction in Th17 cells, and the disease did not rebound. These circumstances are relevant to humans as intervention could be made at early as well as late stages after diagnosis. Overall, these results provide insights on future immunotherapeutic measures of T1D using regulatory cytokines or intervention with an antigen-specific therapy.
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