Reversal of New-Onset Type 1 Diabetes in Mice and Induction of FoxP3+ Regulatory T Cells by Syngeneic Bone Marrow Transplantation.

Objective: Autologous bone marrow transplantation (ABMT) was introduced as a novel strategy to treat new-onset type 1 diabetes (T1D). Induction of CD4+CD25+ FoxP3+T regulatory lymphocytes (Tregs) helps maintain self-tolerance in autoimmune diabetes. Here, we were tying to investigate the effects of syngeneic bone marrow transplantation (syn-BMT) in T1D mice models and to investigate the role of Tregs in this context.

Research design and methods: Syn-BMT was used to mimic the ABMT to T1D patients in human. Fraternal inbred multiple low doses of streptozotocin (mld-SZ) induced diabetic mice were used as both donors (n = 7) and recipients (n = 20). And normal fraternal inbred mice were also used as donors (n=13). After total body irritation to recipient mice, syn-BMT was given either on day 10 or on day 40 of T1D. Blood and urine glucose was observed. On day120 after syn-BMT, glucose tolerance was tested and then mice were killed. Insulin levels in sera were tested by ELISA and pancreata histological and morphometry were analyzed by HE staining. Tregs in spleens were tested by Flow cytometry analysis, FoxP3 protein was tested by western blot, and FoxP3 mRNA was tested by real time PCR.

Results: Syn-BMT, if applied when T1D is new-onset (10 d), can reverse blood glucose to close to normoglycemia without farther relapse, maintain blood insulin levels, improve glucose tolerance and ameliorate pancreata destruction. Syn-BMT leading to recovery of T1D results in the induction of Tregs, increased Foxp3 protein and mRNA expression in both the groups of diabetic mice receiving syn-BMT with either diabetic or normal donors. However, if given on a later disease stage (40 d), although syn-BMT helped reduce blood glucose for about 66 d and improved pancreata histological and morphometry, it showed relapse of diabetes further and decrement of insulin levels. Interestingly, this group did not show the increment of Tregs, Foxp3 protein or mRNA expression.

Conclusions: This study provided a rationale to treat human new-onset T1D with autologous HSC. Syn-BMT, if given when T1D is new-onset, is safe and is able to reverse the diabetic status. The induction of Tregs and Foxp3 in both mRNA and protein levels as the results of syn-BMT, may contribute to the immune tolerance after syn-BMT, and the observed improvement of new-onset T1D.