{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:45:38Z","timestamp":1785908738449,"version":"3.56.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Autologous hematopoietic stem cell transplantation (AHSCT)-based immune system reset (ISR) is conceptually distinct from donor-hematopoietic chimerism: recipient immunity is deeply depleted and rebuilt from recipient-derived hematopoietic stem\/progenitor cells, without intended donor hematopoiesis. This review evaluates whether that platform could support kidney-allograft acceptance under reduced immunosuppression and, in exceptional responders, justify later testing of operational tolerance. We separate four evidence levels: mechanistic observations after AHSCT for autoimmune disease, preclinical hematopoietic-rescue models without intended donor chimerism, human partial-reset\/minimization studies, and true drug-free tolerance. Autoimmune-disease data establish repertoire renewal and regulatory rebalancing, but do not prove alloantigen-specific tolerance. Experimental and early clinical transplant evidence remains limited and heterogeneous. We refine the proposed immune reconstitution-window model as a falsifiable framework in which continuous graft-derived donor-antigen exposure must coincide with a transient period of heightened immune plasticity. Donor antigen may enter this window through kidney transplantation during reconstitution after pretransplant ISR, or may already be present when ISR is applied to a stable recipient with an established allograft. Antigen presence is hypothesized to be necessary, but not sufficient, for donor-specific hyporesponsiveness. The model is linked to measurable targets: reduction of circulating and memory lymphocytes, turnover of donor-reactive clones, recovery of thymic output and naive repertoires, HLA-antibody trajectories interpreted against pretransplant donor-specific antibody status and specificity, absence of molecular or histologic graft injury, and reduced immunosuppression requirements. We also address resistant plasma cells, tissue-resident memory, pathogen-specific immunity, natural-killer-cell missing-self responses, age-dependent thymic recovery, stem-cell source, organ- and donor-type constraints, and kidney-specific safety. Current evidence supports biomarker-gated mechanistic testing in highly selected patients, not routine AHSCT or unmonitored immunosuppression withdrawal.<\/jats:p>","DOI":"10.3389\/fmed.2026.1895856","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:56:01Z","timestamp":1785905761000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Autologous immune system reset for kidney allograft acceptance: mechanisms, evidence, and a testable reconstitution-window model"],"prefix":"10.3389","volume":"13","author":[{"given":"Chunhui","family":"Lyu","sequence":"first","affiliation":[{"name":"Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]},{"name":"Key Laboratory of Organ Transplantation, Ministry of Education","place":["Wuhan, China"]},{"name":"NHC Key Laboratory of Organ 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daqiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]},{"name":"Key Laboratory of Organ Transplantation, Ministry of Education","place":["Wuhan, China"]},{"name":"NHC Key Laboratory of Organ Transplantation","place":["Wuhan, China"]},{"name":"Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences","place":["Wuhan, China"]},{"name":"Hubei Provincial Clinical Research Center for Organ Transplantation","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1097\/SLA.0b013e3181f3efb0","article-title":"Clinical operational tolerance after renal transplantation: 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