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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Chronic Disease, Cyclosporine, Graft Rejection, Heart Transplantation, Histocompatibility Antigens, Immunosuppressive Agents, Intracellular Signaling Peptides and Proteins, Male, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Multiprotein Complexes, Phosphoproteins, Rapamycin-Insensitive Companion of mTOR Protein, Rats, Rats, Inbred ACI, Rats, Wistar, Regulatory-Associated Protein of mTOR, Signal Transduction, Sirolimus, T-Lymphocytes, TOR Serine-Threonine Kinases, Time Factors, rac1 GTP-Binding Protein.
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Does abrogation of chronic rejection in rat model system involve modulation of the mTORC1 and mTORC2 pathways? Context: Current immunosuppressive regimens fail to avert chronic rejection (CR) of transplanted organs; however, selective targeting of actin-cytoskeletal regulators decreases T-cell motility and abrogates CR in rat model system. Administration of mutated class I major histocompatibility complex molecules or selective targeting of the RhoA pathway, which controls T-cell cytoskeletal activity, using Y27632 (a selective Rock1 inhibitor) resulted in reduced T-cell infiltration and abrogation of CR as judged from the neointimal index (13.9±19.7 vs. 45±37.5; P<0.001) and the number of affected vessels (30% vs. 60%; P<0.01). Here, we examined the role of mammalian target of rapamycin (mTOR) pathway in inhibition of CR. A mutated class I major histocompatibility complex molecule that eliminates CR was delivered into ACI recipients of Wistar-Furth hearts at the time of transplantation with subtherapeutic cyclosporine (10 mg/kg on days 0-2). Controls included untreated and cyclosporine A-treated (10 mg/kg on days 0-2) heart allograft recipients. Western blotting and immunostaining showed that rat heart allografts with abolished CR exhibited down-regulation of the RAPA-sensitive mTORC1 components such as mTOR and Raptor and down-regulation of the RAPA-insensitive mTORC2 elements Rictor and Sin1. The mTOR regulator Deptor and its downstream target Rac1 were also inhibited.
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Abrogation of CR in rat model system involves modulation of two mTOR pathways: a RAPA-sensitive mTORC1 pathway regulating cellular proliferation and a RAPA-insensitive mTORC2 pathway regulating T-cell motility. Selective targeting of T-cell actin cytoskeletal pathways shows potential for pathway-targeted immunosuppression therapies. Final Decision: yes