Transplantation tolerance versus immune evasion: Mechanistic divergences and therapeutic frontiers for islet cell replacement

Allogeneic transplantation is encumbered by the toxicities of chronic immunosuppression, driving innovations for lifelong graft acceptance without ongoing therapy. Transplantation tolerance, a recipient-centric strategy, utilizes central deletional processes through mixed hematopoietic chimerism and thymic repertoire sculpting, complemented by peripheral mechanisms such as T cell anergy, exhaustion, apoptotic deletion, and regulatory T cell dominance. Adjunctive costimulatory blockade enhances the latter pathways, yet tolerance remains precarious, susceptible to destabilization by infections or inflammatory perturbations via heterologous immunity. Conversely, immune evasion adopts a product-centric approach, engineering grafts to intrinsically circumvent adaptive allorejection, innate cytotoxicity, and autoimmune recognition and responses. These mechanistic contrasts-dynamic recipient modulation versus robust graft stealth-underscore immune evasion's transformative promise and resilience, with empirical validation for cell and organoid transplantation. This review focusses on islet cell replacement therapy, wherein cadaveric allogeneic islet allografts have been clinically available for over four decades, complemented by recent advancements in stem cell-derived islet products.