Volume 35, No 2, Feb 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 2, February 2025: 132-144   |  Open Access

ORIGINAL ARTICLES

Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation

Yang Liu^{1,2,3,4,5,†} , Hexi Feng^{1,2,3,4,5,†} , Ke Li^{1,2,3,4,5,†} , Ruiyi Li^{1,2,3,4,5,†} , Xiao-Jie Zhang⁶ , Ye Tian⁷ , Yujiang Fang^1,2,3,4,5 , Yanjie Zhou^1,2,3,4,5 , Ling Liu^1,2,3,4,5,* , Xiaoqing Zhang^{1,2,3,4,5,8,*}

¹Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
²Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
³Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
⁴Stem Cell Research Center and Key Laboratory of Neuroregeneration of Shanghai Universities, School of Medicine, Tongji University, Shanghai, China
⁵Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China
⁶Department of Gynaecology, Jing’an District Hospital of Traditional Chinese Medicine, Shanghai, China
⁷School of Foreign Studies, Tongji University, Shanghai, China
⁸Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai, China
^†These authors contributed equally: Yang Liu, Hexi Feng, Ke Li, Ruiyi Li
Correspondence: Ling Liu(lliu@tongji.edu.cn)Xiaoqing Zhang(xqzhang@tongji.edu.cn)

Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%–80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a “donor MHC-specific thymus vaccination” (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 DMTV strategy 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.

https://doi.org/10.1038/s41422-024-01049-5

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