Molecular and cellular pathways involved in the therapeutic functions of MHC molecules; a novel approach for mitigation of chronic rejection

Abstract

The mutated major histocompatibility complex (MHC) class I that contains donor-type epitopes displayed on recipient-type molecule was show- n to inhibit acute and chronic rejection and in-duce indefinite survival of heterotopic cardiac allografts when administered in combination with a sub-therapeutic dose of cyclosporine (CsA) in a rat transplantation model. To eluci-date the molecular pathways involved in the immunosuppressive effects of the mutated MHC molecule, we analyzedgene and protein expres-sion profile during early and late phase follow-ing post-transplantation. Cytoskeletal structure analysis and expression status of Rho GTPase proteins, vacuolar transport and cytoskeleton regulatory pathways involved in immune re-sponse in T and dendritic cells demonstrated the novel mechanism for the abrogation of chronic rejection. Our studies confirm a new role of Rho GTPase pathway in the modification of T cell motility and infiltration of the graft. We discuss these results within the framework of the most recent literature on MHC and molecu-lar machinery controlling T cell functions and dendritic cell antigen presentation