Introduction: Pre-transplant angiogenesis plays a crucial role in subcutaneous islet transplantation. However, concerns have been raised regarding the tissue damage incurred during angiogenesis and the adverse impact of inflammation on islet grafts. Regulatory T cells (Tregs) hold great promise in the field of transplantation medicine. In recent years, it has been suggested that Tregs may not only regulate the immune response and exert anti-inflammatory effects but also promote tissue-specific repair and regeneration. In this study, we aimed to investigate the effect of Treg administration on subcutaneous islet transplantation in both allogeneic and syngeneic experimental models.

Methods: In syngeneic model, we transplanted 500 islets isolated from mice of the identical strain into the dorsal skin of C57/BL6N mice. To induce angiogenesis, we implanted agarose rods containing basic fibroblast growth factor (b-FGF; 50 μg/rod) subcutaneously two weeks before islet transplantation, using STZ-induced diabetic mice as the recipients. On the day of islet transplantation, we infused 1.0×10^6 Tregs isolated from the spleen of C57 BL/6N mice into the recipient's tail vein. We then compared the transplantation outcomes of the Treg-treated group with those of the control group and analyzed the results. In allogeneic model, we engrafted islet cells harvested from BALB/c mice under the dorsal skin of C57/BL6N mice, following  the same procedure as in syngeneic model described above.

Results: The Treg-treated group demonstrated a superior rate of glycemic normalization compared to the control group in the syngeneic model (92.3% versus 64%). Furthermore, the serum cytokine levels of the Treg-treated group were suppressed in comparison to those of the control group one week after transplantation. In the allogeneic model, subcutaneous transplantation of 500 islets did not result in any cases of blood glucose normalization in either the Treg-treated or control groups. However, the transplantation of 1000 islets resulted in temporary graft engraftment in all individuals in the Treg-treated group. The local subcutaneous administration of Tregs around the transplanted islets prolonged the graft implantation period more effectively than systemic administration of Tregs through the tail vein.

Conclusion: In the context of subcutaneous islet transplantation, Tregs may exert a positive impact on the transplantation by mitigating excessive inflammatory responses, thus promoting favorable islet engraftment outcomes. 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.