Most transplants eventually lost to chronic rejection under potent immunosuppression therapies where activation of innate immunity is suspected to play a major role in graft loss. Monocytes and macrophages are major cell types infiltrating the grafts in chronic rejection, but the molecular mechanisms involved are poorly understood. In the present study, we generated mTOR-conditional knockout mice in which deletion of mTOR in macrophages was induced by LyzM-Cre and used this model to examine the role of mTOR in regulating innate immunity in chronic allograft rejection. We demonstrated that in mTOR deleted macrophages, polarization to an M2 phenotype was impaired whereas induction of M1 phenotype was intact, and this impaired M2 induction was related to reduced STAT6 activation. In a heart transplant model in vivo, we found that treatment of wild type C57BL/6 mice with CTLA-4Ig prevented acute rejection of Balb/c heart allograft, but allowed chronic rejection to develop. In this model, there was an extensive macrophage infiltration in chronically rejected heart allografts, and the graft infiltrating macrophages preferentially expressed markers associated with M2 phenotype. Interestingly, treatment of macrophage specific mTOR deleted mice with CTLA4-Ig showed that neointima formation and M2 infiltration were marked ameliorated in the grafts, and as such, the graft survival was marked prolonged (>55 days). These findings highlight the importance of mTOR in regulation of macrophage differentiation in chronic rejection and provide new therapeutic targets in prevention of chronic allograft loss.

CITATION INFORMATION: Zhao Y, Chen W, Lan P, Xiao X, Liu W, Kloc M, Liu Y, Ghobrial R, Gaber O, Li X. Conditional Deletion of mTOR in Myeloid Cells Inhibits Chronic Allograft Rejection – A Novel Role for Macrophages in Transplant Vasculopathy. Am J Transplant. 2016;16 (suppl 3).

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