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.