Increased ?-cell proliferation before immune cell invasion prevents progression of type 1 diabetes.

ABSTRACT: Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of ?-cells1. Restoration of insulin-producing ?-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2-4. Here we report that enhancing ?-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower ?-cell apoptosis, that together protect them from developing T1D. The animals displayed altered ?-cell antigens, and islet transplantation studies showed prolonged graft survival in the NOD-LIRKO model. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented development of diabetes in pre-diabetic NOD mice. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population was observed to underlie the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with activation of TGF-?/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill ?-cells. These data support a previously unidentified observation that initiating ?-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of ?-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

SUBMITTER: Dirice E 

PROVIDER: S-EPMC6696912 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature