Reversal of Autoimmune Diabetes

University Of Missouri-Columbia, Columbia MO

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Abstract

DESCRIPTION (provided by applicant): Type I diabetes (T1D) is a spontaneous autoimmune disease in which the insulin-producing ¿ cells of the pancreatic islets are destroyed as a consequence of immune inflammatory reactions. T helper (Th) lymphocytes specific for ¿ cell-associated self-antigens, such as insulin ¿ (INS) chain or glutamic acid decarboxylase (GAD), play a major role in the development of T1D. Usually, peripheral tolerance keeps these self-reactive T cells harmless. However, in prone mice and susceptible humans, genetic and environmental factors trigger break of tolerance, activation of autoreactive T cells and development of T1D. Specific targeting of diabetogenic T cells represents a viable strategy for therapy of T1D. Recently, we developed an antigen-specific approach that could modulate diabetogenic T cells and reverse T1D in the non-obese diabetic (NOD) mouse. In this approach the nucleotide sequence of GAD206-220 diabetogenic peptide (referred to as GAD2) was genetically engineered into immunoglobulins (Igs) and the resulting Ig-GAD2 chimera was tested for internalization into antigen presenting cells (APCs) via Fc¿ receptors (Fc¿R), presentation to T cells under tolerogenic conditions and protection against T1D. Preliminary results show that Ig-GAD2, although it had a moderate effect when given to mice at the pre-insulitis stage, was effective against the disease at the insulitis as well as the prediabetic stages. Most surprisingly, Ig-GAD2 treatment nullified IL-17 but not IFN¿ responses, eradicated islet infiltration and sustained generation of new ¿- cells leading to restoration of normoglycemia. The hypothesis we wish to put forth for these observations postulates that Ig-GAD2 treatment deviates differentiation of naive T cells away from Th17 or converts differentiated Th17 cells into non-pathogenic Th subsets. As a result, shortage of Th17 cells in the pancreas leads to clearance of islet infiltration and the consequent generation of new ¿ cells either by division of residual ¿ cells or differentiation of pancreatic stem cells. Three aims are proposed to test this hypothesis and evaluate Ig-GAD2 for reversal of the disease at the diabetic stage. Aim 1 will investigate the mechanism by which Ig- GAD2 interferes with Th17 cells. Aim 2 will determine whether the new ¿ cells generated during treatment with Ig-GAD2 emanate from division of residual ¿ cells or differentiation of pancreatic stem cells. And aim 3 will evaluate I-GAD2 alone or in combination with other Ig chimeras for reversal of disease at the diabetic stage. Understanding the mechanism by which antigen-specific therapy leads to suppression of pancreatic inflammation and formation of healthy islets should yield significant information relevant to the development of approaches against T1D.