Background: Chronic rejection is the major obstacle to long-term survival of organ allografts. We study the cellular and molecular pathways involved in the inhibition of chronic rejection in rat cardiac allograft model system in which mutated class I molecule in conjunction with sub-therapeutic dose of cyclosporine (CsA) abrogates chronic rejection. Methods: Mutated molecule was delivered through the portal vein into ACI recipients of WF hearts at the time of transplantation in addition to a 3 days course of oral cyclosporine. Western blots and immunostaining with mTOR pathway components was performed on T cells harvested at 1, 3 and 7 days post-transplantation.

Results: We showed previously that the inhibition of chronic rejection involves a down regulation of RhoA pathway leading to the changes in T cells actin cytoskeleton and motility. Here we show that the inhibition of chronic rejection also involves a down regulation of mTOR and its downstream target Rac1, which similarly to RhoA is the regulator of actin cytoskeleton. Conclusions: Since the mTOR controls, via mTORC2 complex, the RhoA and Rac1 pathways, which are both the regulators of actin organization, these results indicate that a dysregulation of two parallel (RhoA and Rac1) actin pathways plays a role in the inhibition of chronic rejection. This novel finding that inhibiting the chronic rejection of allografts involves disrupting the integrity of T cell actin cytoskeleton via interference with two parallel actin cytoskeleton regulating targets of mTORC2 complex establishes a new paradigm and opens new frontiers in the study of pathway-targeted immunosuppression therapies.

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