Immunomodulation and Regeneration of Islet Beta Cells by Cytokines in Autoimmune Type 1 Diabetes

Abstract

Juvenile or type 1 diabetes (T1D) involves autoimmune-mediated destruction of insulin-producing β cells in the islets of Langerhans in the pancreas. Lack of insulin prevents the absorption and metabolism of glucose throughout the body by interfering with cell signaling. Cytokines have been shown to play a key role in β cell destruction and regulation of autoimmunity in T1D. The multiple roles of cytokines in T1D pathogenesis, regulation, and regeneration of β cells presents both promise and challenge for their use in immunotherapy. We found that mycobacterial adjuvants induce various regulatory T cells in the non-obese diabetic (NOD) mouse model of T1D. Cytokines produced by these cells not only regulate innate and adaptive immunity but also prevent the development of diabetes and partially restored normoglycemia in diabetic NOD mice. We discovered that adjuvant immunotherapy upregulated Regenerating (Reg) genes in the islets and induced interleukin 22 (IL-22)-producing Th17 cells. IL-22 is known to upregulate Reg gene expression in islets and could potentially induce regeneration of β cells and prevent their apoptosis. Therefore, cytokines both induce and regulate T1D and have the potential to regenerate and preserve insulin-producing β cells in the islets.