Immunomodulatory therapies to prevent transplant rejection in composite tissue allotransplantation: Current status and future prospects

Composite tissue allotransplantation (CTA), including such surgery as hand transplantation and facial transplantation, can restore functionality and quality of life of patients with moderate and severe tissue loss. Nevertheless, it is also subject to immunological barriers once again, especially in the form of acute and chronic rejection due to the high immunogenicity of composite tissues, most notably of skin. Contemporary immunomodulatory approaches are based on induction drugs (e.g., anti-thymocyte globulin), maintenance intervention (e.g., tacrolimus, mycophenolate mofetil, corticosteroids) as well as rescue therapy against acute rejection. The solutions to these problems are associated with limitations due to considerable toxicities (infections, malignancies, and nephrotoxicity), with partial prevention of chronic graft vasculopathy despite providing an effective way to prevent early rejection. The new strategies that are promising for achieving an advantage in terms of tolerance and minimizing systemic immunosuppression include mixed chimerism, regulatory T-cell-based therapeutics, costimulation blockade, and localized drug delivery platforms. Gene editing and biomaterials can also present a novel approach to regulating immunogenicity. Its future directions include personalized immunosuppression using pharmacogenomics, instance tracking of immune status, and artificial intelligence-based predictive models. The pinnacle will be the development of immune tolerance, which may make CTA immunosuppression-free. This review compares clinical outcomes, highlights limitations, and examines new therapies using data from international registries and ongoing trials. It highlights the importance of multidisciplinary efforts in promoting translational research and its associated protocols. These innovations can revolutionize the field, increasing the longevity of grafts and improving patient outcomes by overcoming immunological barriers, thereby reaching a broader audience worldwide with CTA.