Role of mTOR C1/C2 pathways involve in abrogation of chronic rejection in rat heart transplantation model

Abstract

Objective To study the expression of the components of the mammalian rapamycin target protein (mTOR) pathway in T lymphocytes in rats with chronic rejection (CR), and to explore the role of mTOR pathway in the inhibition of CR. Methods ACI rat recipients received intraperitoneal ectopic cardiac transplantation with Wistar-Furth rat hearts. In the experimental group, a mutated class I major histocompatibility complex (MHC I) that can eliminate CR was delivered into recipients prior-operation, and a sub-therapeutic cyclosporine A (CsA) (10 mg/kg, 3 d) was also administered. In the experimental control group, the heart allograft recipients were treated with sub-therapeutic CsA (10 mg/kg, 3 d). The blank controls were the untreated recipients. Each group was divided into three subgroups (5 rats in each subgroup) according to the sacrifice time on the postoperative 1st, 3rd and 7th days. The spleen samples were taken for T cell extraction and Western blot analysis. Results Western blot results showed that rat heart allografts with abolished CR exhibited downregulation of the RAPA-sensitive mTORC1 elements including mTOR and Raptor, and down-regulation of the RAPA-insensitive mTORC2 elements including Rictor and Sin1. Conclusions Abrogation of CR in rat model system involves modulation of mTOR C1 and mTOR C2 pathways. The mTOR C1 pathway regulates cellular proliferation and the mTORC2 pathway regulates T-cell motility. Selective targeting of T-cell actin cytoskeletal pathways shows potential for pathway-targeted immunosuppression therapies. Key words: Chronic rejection; Transplantation; Immune tolerance; Actin cytoskeleton