Epigenetic Modification at the FOXP3 Locus and IL-2 Signaling to Induce Regulatory T Cells in Type I Diabetes Immunotherapy
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 complications2-4. Treatment options include insulin therapy, and recently, research has focused on immunotherapy including regulatory T cells (Treg) induction5-6. 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+CD25hFOXP3+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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- Schuster C, Jonas F, Zhao F, and Kissler S. Peripherally‐induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model. European Journal of Immunology. 2018; Accepted Author manuscript. https://onlinelibrary.wiley.com.ezproxy.library.tamu.edu/doi/epdf /10.1002/eji.201847498. Accessed April 21, 2018.
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- Kehrmann J, Tatura R, Zeschnigk M, et al. Impact of 5-aza-2′-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells. Immunology. 2014;142(3):384-395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080954/. Accessed April 22, 2018.
- Bell CJM, Sun Y, Nowak UM, et al. Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. Journal of Autoimmunity. 2015;56:66-80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298360/. Accessed April 22, 2018.
- Rosenzwajg M, Churlaud G, Mallone R, et al. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. Journal of Autoimmunity. 2015;58:48–58. http://hal.upmc.fr/hal-01112156/document. Accessed April 22, 2018.