Abstract
chronic rejection or transplant vasculopathy is a major problem in the clinic hindering long-term transplant survival. Chronic rejection primarily targets the graft vasculature, but the exact mechanism underlying the slow and progressive vasculature damage in transplanted organs remains poorly defined. In the present study, we addressed the role of macrophages in chronic allograft rejection in a mouse heart transplant model. We found that treatment of B6 recipients with a single dose of CTLA-4Ig prolonged the survival of Balb/c heart allografts(MST=35d) as compared to untreated controls (MST=8 days). Histologically, the CTLA-4Ig treated grafts showed signs of extensive chronic rejection characterized by heavy leukocyte infiltration and prominent neointima formation. Phenotypically, macrophages were a key infiltrating cell type in the vascular lesions in the grafts. Further studies revealed a M2 (F4/80+CD206+) phenotype for grafting infiltrating macrophages. An increased number of M2 macrophages were also detected in the spleen of recipient mice that experienced chronic rejection. We polarized macrophages in vitro to M1 and M2 subsets and systemically screened for differences and specific pathways that could be targeted for inhibition of M1 and M2 macrophages. We showed that when macrophages were polarized to a M2 phenotype, they preferentially expressedP2x7 receptor, a member of P2x family receptors that sense metabolites. We also found that oxidized ATP (P2x7R inhibitor)could effectively inhibit M2 induction in vitro. Importantly, in the heart transplant model, CTLA-4Ig plus oxidized ATP induced long-term heart allograft survival(MST>100 days), which was associated with markedly reduced neointima generation in the grafts, and prevention of chronic rejection was associated with significant inhibition of M2 macrophages in situ. Our studies identified a previously unknown mechanism of transplant vasculopathy and pinpointed as a molecular target in the inhibition of infiltrating M2 macrophages and chronic rejection.
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