Reversal of Autoimmune Diabetes

Zaghouani, Habib

Abstract

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.

Public Health Relevance

The study proposes to investigate the mechanisms by which an antigen specific approach clears pancreatic islet infiltration and drives the formation of new insulin producing Beta cells at advanced stages of the disease. Progress at the level of suppression of inflammation and its relationship with the restoration of healthy islets should move the field forward and yield information relevant to the development of drugs to reverse type 1 diabetes. The Ig delivery system is ideal for the development of antigen-specific approach against the disease as it overcomes the short half-life of peptide, increases peptide presentation and augments the efficacy of pathogenic T cell targeting. Moreover, it offers a system suitable for understanding mechanisms of both tolerance and ? cell generation. Overall, an antigen specific approach for reversal of type I diabetes would be the ideal strategy against the disease as it would target pathogenic T cells with little effect on the protective function of he immune system.