Regulatory T-cells technology and vascularized composite allotransplantation: A scoping review

Vascularized composite allotransplantation (VCA) offers life changing reconstructive options for patients with traumatic injuries or congenital defects, restoring function and appearance. Its success is limited by strong immune responses, and long-term immunosuppression carries significant risks. Emerging cellular therapies, particularly regulatory T cells (Tregs) offer promising strategies to mitigate rejection and reduce immunosuppression dependence. Preclinical studies in animal models suggest that Treg-based approaches may improve graft survival and potentially reduce the need for conventional immunosuppression in VCA.

An all-time literature search of Regulatory T cell therapy in Vascularized Composite Allotransplantation in animal models was performed on the following electronic databases: PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and TRIP Database until August 2025. Data was analyzed for graft survival, regulatory T cell activity, chimerism, and tolerance mechanisms.

A total of 2182 studies were screened across six databases, of which 13 met eligibility criteria and 5 were selected focusing on Treg therapy in VCA animal models. Treg therapy consistently prolonged graft survival (>200 days), promoted chimerism, reduced inflammation, and induced donor specific tolerance. CAR-Tregs demonstrated antigen-specific tolerance, while mesenchymal stem cells (MSCs) enhanced immunomodulation, particularly under hypoxic preconditioning. Other cellular therapies, including hematopoietic stem cells (HSC), also improved graft acceptance, demonstrating their potential as adjuncts or alternatives to long term immunosuppression.

Cellular therapies, especially Treg based approaches such as adoptive transfer and local enrichment or induction of Tregs, consistently promote immune tolerance, suppress graft rejection, and extend allograft survival in VCA animal models. These approaches reduce the need for long term immunosuppression and create a pro-tolerogenic environment, supporting their translational potential. However, further clinical validation is required to optimize dosing, persistence and safety for application in human VCA recipients.