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

Yue Zhao, Song Chen, Peixiang Lan, Chenglin Wu, Yaling Dou, Xiang Xiao, Zhiqiang Zhang, Laurie Minze, Xiaoshun He, Wenhao Chen, Xian C Li

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2018 Mar

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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 (LysMCre Traf6 fl/fl ) or mTOR (LysMCre Mtorfl/fl ) did not affect acute allograft rejection. However, treatment of LysMCre Mtorfl/fl recipients with CTLA4-Ig induced long-term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysMCre Traf6 fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig-treated LysMCre 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 LysMCre Mtorfl/fl recipients expressed high levels of PD-L1, and that PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysMCre Mtorfl/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. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Citation

Yue Zhao, Song Chen, Peixiang Lan, Chenglin Wu, Yaling Dou, Xiang Xiao, Zhiqiang Zhang, Laurie Minze, Xiaoshun He, Wenhao Chen, Xian C Li. Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Mar;18(3):604-616