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However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%\u201380% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a \u201cdonor MHC-specific thymus vaccination\u201d (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL\/6-MHC and BALB\/c-MHC dual immunocompatible mice via thymus vaccination of C57BL\/6-MHC into the BALB\/c thymus and observed long-term graft tolerance after transplantation of C57BL\/6 skin and C57BL\/6 mouse embryonic stem cells into the vaccinated BALB\/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the\u00a0DMTV\u00a0strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.<\/jats:p>","DOI":"10.1038\/s41422-024-01049-5","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T20:01:39Z","timestamp":1735848099000},"page":"132-144","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation"],"prefix":"10.1038","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7647-3422","authenticated-orcid":false,"given":"Yang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujiang","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-1893","authenticated-orcid":false,"given":"Xiaoqing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,3]]},"reference":[{"key":"1049_CR1","unstructured":"Global Observatory on Donation and Transplantation (GODT). 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