PMID- 37105316 OWN - NLM STAT- MEDLINE DCOM- 20230814 LR - 20230816 IS - 1600-6143 (Electronic) IS - 1600-6135 (Linking) VI - 23 IP - 8 DP - 2023 Aug TI - Donor programmed cell death 1 ligand 1 is required for organ transplant tolerance in major histocompatibility complex-mismatched mixed chimeras although programmed cell death 1 ligand 1 and major histocompatibility complex class II are not required for inducing chimerism. PG - 1116-1129 LID - S1600-6135(23)00426-4 [pii] LID - 10.1016/j.ajt.2023.04.022 [doi] AB - Induction of major histocompatibility complex (MHC) human leukocyte antigen (HLA)-mismatched mixed chimerism is a promising approach for organ transplantation tolerance; however, human leukocyte antigen-mismatched stable mixed chimerism has not been achieved in the clinic. Tolerogenic dendritic cell (DC) expression of MHC class II (MHC II) and programmed cell death 1 ligand 1 (PD-L1) is important for immune tolerance, but whether donor-MHC II or PD-L1 is required for the induction of stable MHC-mismatched mixed chimerism and transplant tolerance is unclear. Here, we show that a clinically applicable radiation-free regimen can establish stable MHC-mismatched mixed chimerism and organ transplant tolerance in murine models. Induction of MHC-mismatched mixed chimerism does not require donor cell expression of MHC II or PD-L1, but donor-type organ transplant tolerance in the mixed chimeras (MC) requires the donor hematopoietic cells and the organ transplants to express PD-L1. The PD-L1 expressed by donor hematopoietic cells and the programmed cell death 1 expressed by host cells augment host-type donor-reactive CD4(+) and CD8(+) T cell anergy/exhaustion and differentiation into peripheral regulatory T (pTreg) cells in association with the organ transplant tolerance in the MC. Conversely, host-type Treg cells augment the expansion of donor-type tolerogenic CD8(+) DCs that express PD-L1. These results indicate that PD-L1 expressed by donor-type tolerogenic DCs and expansion of host-type pTreg cells in MHC-mismatched MCs play critical roles in mediating organ transplant tolerance. CI - Copyright (c) 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved. FAU - Huang, Yaxun AU - Huang Y AD - Department of Liver Transplantation, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Wu, Xiwei AU - Wu X AD - Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Tang, Shanshan AU - Tang S AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Wu, Huiqing AU - Wu H AD - Department of Pathology, City of Hope National Medical Center, Duarte, California, USA. FAU - Nasri, Ubaydah AU - Nasri U AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Qin, Qi AU - Qin Q AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Song, Qingxiao AU - Song Q AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Wang, Bixin AU - Wang B AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Fujian Medical University Center of Translational Hematology, Fujian Medical University Union Hospital, Fuzhou, China. FAU - Tao, Hansen AU - Tao H AD - Arthur Riggs Diabetes and Metabolism Research Institute, Summer Student Academy of City of Hope, Duarte, California, USA. FAU - Chong, Anita S AU - Chong AS AD - The section of Transplantation, Department of Surgery, the University of Chicago, Chicago, Illinois, USA. FAU - Riggs, Arthur D AU - Riggs AD AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. FAU - Zeng, Defu AU - Zeng D AD - Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA; Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA. Electronic address: dzeng@coh.org. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230425 PL - United States TA - Am J Transplant JT - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons JID - 100968638 RN - 0 (B7-H1 Antigen) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (HLA Antigens) SB - IM MH - Mice MH - Humans MH - Animals MH - *Transplantation Tolerance MH - B7-H1 Antigen MH - Chimerism MH - Histocompatibility Antigens Class II MH - Major Histocompatibility Complex MH - HLA Antigens MH - Immune Tolerance MH - *Organ Transplantation MH - Transplantation Chimera MH - Bone Marrow Transplantation/methods OTO - NOTNLM OT - MHC II OT - PD-L1 OT - mixed chimerism OT - organ transplant tolerance EDAT- 2023/04/28 00:42 MHDA- 2023/08/14 06:41 CRDT- 2023/04/27 19:23 PHST- 2022/11/16 00:00 [received] PHST- 2023/04/19 00:00 [revised] PHST- 2023/04/19 00:00 [accepted] PHST- 2023/08/14 06:41 [medline] PHST- 2023/04/28 00:42 [pubmed] PHST- 2023/04/27 19:23 [entrez] AID - S1600-6135(23)00426-4 [pii] AID - 10.1016/j.ajt.2023.04.022 [doi] PST - ppublish SO - Am J Transplant. 2023 Aug;23(8):1116-1129. doi: 10.1016/j.ajt.2023.04.022. Epub 2023 Apr 25.