Treatment of Type I Diabetes in the NOD Mouse with Syngeneic Cord Blood Stem Cells

Abstract

Human type 1 diabetes mellitus occurs due to chronic inflammation with lymphocytic infiltration and (usually) the presence of antibodies against insulin and characteristic islet cell proteins (e.g., GAD). This autoimmune process destroys the islets of Langerhans (including the beta cells) leading to insulin insufficiency. In several studies to date diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes has either been prevented or reversed by allogeneic transplantation of stem cells derived from mouse bone marrow or spleen. Immunosuppressive regimens have been ablative in some studies, but non-ablative regimes have been used in others. With non-ablative regimens, recipient mice develop chimeric immune systems. In addition, two recent clinical trials using stem cells have shown similar benefit for human patients with type 1 diabetes. We investigated whether stem cells isolated from genetically identical, but non-diabetic neonatal mouse pups (i.e., the mouse equivalent of human cord blood stem cells) would reverse diabetes when transfused into NOD mouse recipients which have already developed hyperglycemia. It was observed that cord blood stem cell infusion after diabetic conversion resulted in reversal of hyperglycemia whether given with or without the immune ablative drug, cytoxan. However, cytoxan alone had no beneficial effect. Stem cell-treated mice also lived longer than untreated mice. In these studies it was not possible to demonstrate islet cell regeneration resulting from the infused stem cells. These experiments provide evidence that cord blood stem cells may be suitable for improving or eliminating the autoimmune process in human type 1 diabetes patients, and thereby modulating their disease. However, additional studies are needed to clarify the mechanisms behind these observations.