Immunological considerations and outcomes in cross-sex vascularized composite allotransplantation

Abstract

Vascularized composite allotransplantation (VCA) has transformed reconstructive surgery for patients with severe tissue defects. Nonetheless, donor shortages remain a major limitation. Cross-sex VCA (CS-VCA) has been proposed as a means of expanding the donor pool, but concerns persist regarding potentially heightened rejection risks in sex-mismatched transplants. This review examines published adult CS-VCA cases up to May 2025. The primary outcomes analyzed were acute rejection episodes, allograft survival, immunological complications, and sequelae affecting form and function. Nine CS-VCA cases were identified (six upper extremity, one lower extremity, and two abdominal wall transplants). Eight involved female donors (median age, 47 years) and male recipients (median age, 30 years). Acute rejection occurred in five of nine cases; however, 11 of 13 allografts remained viable at follow-up (6-41 months) under immunosuppressive therapy. Two cases developed vascular complications, resulting in technical failure and partial amputation, respectively. Higher human leukocyte antigen (HLA) mismatches (mean, 5) were associated with complications, while fewer mismatches (mean, 3) correlated with better outcomes. In contrast to trends in solid organ transplantation, female-to-male CS-VCA demonstrated relatively favorable outcomes in the limited cases reported. These findings suggest that CS-VCA may be a feasible strategy to expand the VCA donor pool, provided that patient selection is careful, ABO/Rh and HLA compatibility are prioritized, and rigorous immunological monitoring is maintained. Further studies should investigate sex-specific immune mechanisms to optimize long-term success rates.

Keywords: Graft rejection; Lower extremities; Sex factors; Upper extremities; Vascularized composite allotransplantation.