Reshma George

Introduction: Type 1 Diabetes (T1D) is a chronic disease characterized by autoimmune destruction of pancreatic beta cells with lymphocyte infiltration that leads to decreased insulin production. Over 1.25 million Americans currently have the disease, and 40,000 new diagnoses are made every year¹. Individuals with T1D present with increased thirst, blurred vision, numbness and tingling, and other complications^2-4. Treatment options include insulin therapy, and recently, research has focused on immunotherapy including regulatory T cells (Treg) induction^5-6. The pancreatic beta cells in T1D are destroyed by self-reactive CD4+ and CD8+ T cells, which are normally suppressed by Treg cells⁷. The FOXP3 gene and IL-2 signaling are necessary for the proper production and functioning of Treg cells, and deficiencies in either can predispose individuals to T1D⁷. Mice with the FOXP3 gene CNS1 knockout showed decreased peripheral Treg cells and an increased risk for T1D⁸. Consequently, epigenetic modifications of the FOXP3 gene and enhanced IL-2 signaling have been shown to increase Treg cells and reduce the risk of T1D. Methods: CD4⁺CD25⁻T cells were taken from peripheral blood mononuclear cells of healthy adults and treated with DNA methyltransferase inhibitor 5-azacytidine and evaluated for CD4⁺CD25^hFOXP3⁺Treg cell levels ⁹.  In a similar study, some of the CD4⁺CD25⁻T cells were treated with epigallocatechin-3-gallate instead¹⁰. 2 ultra-low doses of long-half life IL-2 fusion protein molecules were used to treat monkeys and compared to the clinically approved IL-2 molecule, Proleukin, in the induction of Treg cells¹¹. In one clinical study, T1D patients were treated with different doses of IL-2 for 5 consecutive days, and the effects on the peripheral blood mononuclear cells were evaluated¹². Results: The CD4⁺CD25⁻T cells treated with 5-Aza proliferated and showed expression of FOXP3 gene and Treg cell activity⁹. Epigallocatechin-3-gallate did not induce hypomethylation of the Treg cell genes¹⁰. The 2 ultra-low doses of long-half life IL-2 fusion protein molecules prolonged Treg cell expansion with pSTAT5a induction and increased expression of CD25, FOXP3 and Ki-67¹¹. Further, the side effect of eosinophilia associated with Proleukin was not observed¹¹. IL-2 doses of 0.3-3 MIU/day was safe to effectively induce Treg cell proliferation¹². However, at 3 MIU/day NK cells were also expanded leading to mild/moderate side effects¹². Conclusion: Treg cell induction plays a significant role in T1D diabetes. Further research on effective epigenetic modification mechanisms and IL-2 signaling may promote Treg cell induction as a treatment mechanism for T1D patients.

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