Introduction: For the success of subcutaneous islet transplantation, it is crucial to control inflammation and immune responses occurring during the transplantation.  In subcutaneous islet transplantation, while an inflammatory phase is necessary for vascularization of the transplant site, excessive inflammation after angiogenesis have negative effect on the transplant environment. We investigate the effects of administering regulatory T cells (Tregs), which have anti-inflammatory and immunosuppressive functions, on subcutaneous islet transplantation.
Method: To induce angiogenesis, agarose rods containing basic fibroblast growth factor (50μg/rod) were subcutaneously implanted in mice with diabetes as recipients two weeks prior to islet transplantation. In syngeneic model, 500 islets isolated from mice of the same strain were transplanted under the dorsal skin of C57/BL6N mice. On the day of islet transplantation, 1.0×10^6 Tregs isolated from the spleen of C57 BL/6N mice were either infused into the recipient's tail vein (systemic administration group : B) or co-transplanted around the graft islets (co-transplantation group : C). In allogeneic model, islets derived from BALB/c mice were transplanted under the dorsal skin of C57/BL6N mice following the same procedure as in syngeneic model described above.
Results: In the syngeneic model, the Treg-treated group demonstrated a superior engraftment rate in comparison to the control group (group A) (group C: 100%, group B: 92.3%, group A: 64%, respectively). The median engraftment duration was 10 days in group C, 23 days in group B, and 22 days in group A, with a significant reduction noted in group C (C vs A: P=0.0042, C vs B: P=0.0049, Steel-Dwass test). In the allogeneic model, no engraftment was observed under the condition of 500 islets. With 1000 islets, temporary engraftment was achieved in all cases within the Treg-treated group. The median graft survival time was 9 days in group C, 5 days in group B, and 2 days in group A, with the longest extension observed in group C. Furthermore, in the syngeneic model, the Treg-treated group showed low levels of TNFα and IFNγ in the serum one week after transplantation, while in the allogeneic model, the same cytokine concentrations were lower in the Treg-treated group on the day after transplantation.
Conclusion: In the context of subcutaneous islet transplantation, Tregs have the potential to ameliorate excessive inflammatory responses, thereby fostering favorable islet engraftment outcomes. Further research is needed on the mechanisms of immune regulation by Tregs in allogeneic model. A comprehensive evaluation of Treg mechanisms in subcutaneous islet transplantation would enable us to delineate the optimal conditions for achieving successful islet engraftment, as well as to explore the potential utility of Treg-based therapeutic interventions.