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Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model.

Research paper by Yue Y Zhao, Song S Chen, Peixiang P Lan, Chenglin C Wu, Yaling Y Dou, Xiang X Xiao, Zhiqiang Z Zhang, Laurie L Minze, Xiaoshun X He, Wenhao W Chen, Xian C XC Li

Indexed on: 19 Oct '17Published on: 19 Oct '17Published in: American Journal of Transplantation



Abstract

Macrophages infiltrating the allografts are heterogeneous, consisting of pro-inflammatory (M1 cells) as well as anti-inflammatory and fibrogenic phenotypes (M2 cells); they affect transplant outcomes via diverse mechanisms. Herein, we found that macrophage polarization into M1 and M2 subsets was critically dependent on TRAF6 and 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 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 in preventing chronic allograft rejection and that graft survival under such conditions is dependent on the PD-1/PD-L1 co-inhibitory pathway. This article is protected by copyright. All rights reserved.