Characterization and Immunomodulation of Regulatory T cells in Type 1 Diabetes

Goudy, Kevin Scott

Characterization and Immunomodulation of Regulatory T cells in Type 1 Diabetes Public Deposited

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March 20, 2019

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Goudy, Kevin Scott
- Affiliation: School of Medicine, Department of Microbiology and Immunology

Abstract

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disorder characterized by the complete destruction of the insulin-producing pancreatic β cells. The result of β cell loss leads to life-long insulin injections in order to maintain blood glucose levels, and is associated with both micro-vascular and macro-vascular diseases. Disease onset is related to a genetic predisposition, environmental factors, and a cell-mediated immunophenotype. Previous studies using the non-obese diabetic mouse (NOD) suggest that T1D can be prevented by the administration of immunoregulatory proteins that induce/expand both antigen specific and antigen non-specific regulatory cells. The aims of the studies described within are to; i.) test the hypothesis that antigen-specific therapies can prevent diabetes, and ii) to understand the cause(s) of immunoregulatory T cell deficiency in diabetes development. Results from our first study demonstrate that gene therapy with pDNA encoding the β cell protein gluatamic acid decarboxyasle 65 (GAD65) via gene gun significantly prevents diabetes onset in the NOD mouse. Diabetes protection was attributed to the induction of interleukin-4 secreting immunoregulatory T cells. We also discovered that delivery of the same construct via intra-muscularly injection exacerbated diabetes by the preferentially induction of pathogenic type 1 T effector cells. Therefore, our findings show that the route of delivery of pDNA encoding autoantigens is integral in shaping the type of effector cell response. Our second study illustrates that T1D can be regulated by the differential expression of the il2 gene located in the Idd3 locus of the NOD mouse genome. We found that reduced IL-2 production by NOD CD4+ T cells resulted in ~two-fold less induction of FoxP3-expressing regulatory T cells that are critical for regulating autoimmunity. Furthermore, we described a new role for IL-21 whereby IL-21 negatively regulates IL-2 production by CD4+ T cells, thus, perpetuating the inhibition of regulatory T cells. Most importantly, we successfully devised an IL-2 therapy regimen for NOD mice that overcomes the regulatory T cell deficiency which could lead to a new therapeutic approach to prevent and/or treat T1D in humans.

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