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Although effective early, this strategy does not prevent chronic rejection and cannot account for operational tolerance, failure of perfectly HLA\u2010matched grafts, or the occasional spontaneous acceptance of a fully mismatched organ. The adaptation model of immunity offers a different lens. In the thymus, \u201ccentral adaptation\u201d programs T cells to recognise self\u2010peptide\u2013MHC (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\u2010oriented circuitry can operate. Autografts and isografts arrive with their own extracellular\u2010matrix (ECM) \u201cmemory\u201d, and recipient T cells immediately recognise their pMHC, triggering tissue\u2010remodelling responses. Allografts must adapt to new ECM\u2014a 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\u2010presentation, during which the graft relies on donor\u2010derived tissue\u2010resident memory T cells (T<jats:sub>RM<\/jats:sub>) to maintain integrity. Therapeutically, interventions that preserve or expand graft\u2010borne T<jats:sub>RM<\/jats:sub>, or that pharmacologically enhance adaptation\u2010receptor signalling, could hasten this donor\u2010to\u2010host reprogramming. By replacing blanket immunosuppression with targeted promotion of tissue\u2010remodelling immunity, the adaptation model charts a path toward long\u2010term graft survival without the lifelong risks of today's regimens.<\/jats:p>","DOI":"10.1111\/sji.70045","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T06:14:02Z","timestamp":1753683242000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Redefining the Immunobiology of Organ Transplantation for New Clinical Horizons"],"prefix":"10.1111","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7511-2953","authenticated-orcid":false,"given":"Masoud H.","family":"Manjili","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Virginia Commonwealth University (VCU) School of Medicine  Richmond Virginia USA"},{"name":"VCU Massey Comprehensive Cancer Center  Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.2014"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e3181f3efb0"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2008.02159.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2010.12.004"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2015.200"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/sji.13172"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200672"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp19X704441"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/jhmas\/XXXVII.3.269"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mjafi.2023.08.013"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-195809000-00004"},{"key":"e_1_2_9_14_1","first-page":"176","article-title":"The Behaviour and Fate of Skin Autografts and Skin Homografts in Rabbits: A Report to the War Wounds Committee of the Medical Research Council","volume":"78","author":"Medawar P. 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