Redefining the Immunobiology of Organ Transplantation for New Clinical Horizons

Traditional organ transplantation relies on the Self–Non‐self (SNS) model of immunity, focusing on donor–recipient compatibility and aggressive immunosuppression to prevent acute rejection. Although effective early, this strategy does not prevent chronic rejection and cannot account for operational tolerance, failure of perfectly HLA‐matched grafts, or the occasional spontaneous acceptance of a fully mismatched organ. The adaptation model of immunity offers a different lens. In the thymus, “central adaptation” programs T cells to recognise self‐peptide–MHC (pMHC) so they can later recognise different tissues to facilitate tissue repair and homeostasis. Whether a graft thrives or fails depends on how quickly this self‐oriented circuitry can operate. Autografts and isografts arrive with their own extracellular‐matrix (ECM) “memory”, and recipient T cells immediately recognise their pMHC, triggering tissue‐remodelling responses. Allografts must adapt to new ECM—a transition that is associated higher levels of graft injury allowing indirect antigen presentation. Until adaptation is complete, recipient T cells mount cytotoxic rather than reparative responses because of antigen cross‐presentation, during which the graft relies on donor‐derived tissue‐resident memory T cells (T RM ) to maintain integrity. Therapeutically, interventions that preserve or expand graft‐borne T RM , or that pharmacologically enhance adaptation‐receptor signalling, could hasten this donor‐to‐host reprogramming. By replacing blanket immunosuppression with targeted promotion of tissue‐remodelling immunity, the adaptation model charts a path toward long‐term graft survival without the lifelong risks of today's regimens.