Anti-diabetic actions of carbon monoxide-releasing molecule (CORM)-A1: Immunomodulation and regeneration of islet beta cells.

We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as well as beta cell regeneration. CORM-A1 (2 mg/kg/day) was administered for 10 days to mice induced with MLDS and/or depleted of low dose cyclophosphamide (CY)-sensitive FoxP3+ T regulatory (Treg) cells. Besides monitoring hyperglycaemia, ex vivo analysis of spleen, pancreatic lymph nodes (PLN) and pancreas was performed at the end of treatment. In CORM-A1-treated MLDS-induced mice the improvement of hyperglycaemia was observed only without depletion of CY-sensitive FoxP3+ Treg cells. This was accompanied by decreased levels of interleukin (IL)-12, IL-2 and early activation marker CD25 in the spleen and PLN and increased transforming growth factor (TGF)-β, resulting in reduced lymphocyte proliferation in both organs. In parallel, decreased transcript levels of IL-2, but increased mRNA expression of TGF-β, accompanied with up-regulation of Ki-67 protein expression was observed within pancreas. Together, the data suggested that besides the immunomodulatory potential, CORM-A1 probably induces beta cell regeneration.