PMID- 29044999 OWN - NLM STAT- MEDLINE DCOM- 20191112 LR - 20230124 IS - 1600-6143 (Electronic) IS - 1600-6135 (Print) IS - 1600-6135 (Linking) VI - 18 IP - 3 DP - 2018 Mar TI - Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model. PG - 604-616 LID - 10.1111/ajt.14543 [doi] AB - Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor-associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysM(C)(re) Traf6 (fl/fl) ) or mTOR (LysM(C)(re) Mtor(fl/fl) ) did not affect acute allograft rejection. However, treatment of LysM(C)(re) Mtor(fl/fl) recipients with CTLA4-Ig induced long-term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysM(C)(re) Traf6 (fl/fl) recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig-treated LysM(C)(re) Traf6 (fl/fl) mice was similar to that of CTLA4-Ig-treated wild-type B6 recipients. Mechanistically, we found that the graft-infiltrating macrophages in LysM(C)(re) Mtor(fl/fl) recipients expressed high levels of PD-L1, and that PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysM(C)(re) Mtor(fl/fl) recipients. Our findings demonstrate that targeting mTOR-dependent M2 cells is critical for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD-1/PD-L1 coinhibitory pathway. CI - (c) 2017 The American Society of Transplantation and the American Society of Transplant Surgeons. FAU - Zhao, Yue AU - Zhao Y AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Chen, Song AU - Chen S AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Lan, Peixiang AU - Lan P AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Wu, Chenglin AU - Wu C AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. AD - Sun Yet-sun University First Affiliated Hospital, Guangzhou, China. FAU - Dou, Yaling AU - Dou Y AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Xiao, Xiang AU - Xiao X AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Zhang, Zhiqiang AU - Zhang Z AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - Minze, Laurie AU - Minze L AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. FAU - He, Xiaoshun AU - He X AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. AD - Sun Yet-sun University First Affiliated Hospital, Guangzhou, China. FAU - Chen, Wenhao AU - Chen W AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. AD - Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA. FAU - Li, Xian C AU - Li XC AD - Immunobiology & Transplant Science Center, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA. AD - Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA. LA - eng GR - R01 AI080779/AI/NIAID NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171123 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 (TNF Receptor-Associated Factor 6) RN - 0 (TRAF6 protein, mouse) RN - 7D0YB67S97 (Abatacept) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Abatacept/metabolism MH - Allografts MH - Animals MH - CD8-Positive T-Lymphocytes MH - *Disease Models, Animal MH - Graft Rejection/etiology/pathology/*prevention & control MH - Graft Survival/*immunology MH - Heart Transplantation/*adverse effects MH - Macrophages/*immunology/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Knockout MH - TNF Receptor-Associated Factor 6/*physiology MH - TOR Serine-Threonine Kinases/*physiology PMC - PMC5820161 MID - NIHMS913362 OTO - NOTNLM OT - basic (laboratory) research/science OT - heart (allograft) function/dysfunction OT - heart transplantation/cardiology OT - macrophage/monocyte biology: differentiation/maturation OT - rejection: chronic OT - vasculopathy COIS- Disclosure: The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. EDAT- 2017/10/19 06:00 MHDA- 2019/11/13 06:00 PMCR- 2019/03/01 CRDT- 2017/10/19 06:00 PHST- 2017/08/23 00:00 [received] PHST- 2017/09/19 00:00 [revised] PHST- 2017/10/06 00:00 [accepted] PHST- 2017/10/19 06:00 [pubmed] PHST- 2019/11/13 06:00 [medline] PHST- 2017/10/19 06:00 [entrez] PHST- 2019/03/01 00:00 [pmc-release] AID - S1600-6135(22)09456-4 [pii] AID - 10.1111/ajt.14543 [doi] PST - ppublish SO - Am J Transplant. 2018 Mar;18(3):604-616. doi: 10.1111/ajt.14543. Epub 2017 Nov 23.