Objective. Chronic rejection remains the main obstacle in the long-term success of organ transplantation. The long-term survival of allografted hearts is limited by a progressive fibroproliferative disease and occlusion of the graft vessels. This disease known as cardiac transplant vasculopathy (TV) occurs in 40-45% of recipients at 5 years following transplantation. Thus, our goal was to uncover the mechanisms of chronic rejection, which will undoubtedly revolutionize heart transplant medicine. Our previous studies in rat cardiac allograft model system show that using a RhoA/ROCK pathway inhibitor Y-27632 resulted in inhibition of chronic rejection. Methods. We used Balb/c to B6 combination of mouse heterotopic cardiac allograft model system. CTLA4-Ig was delivered ip at 0.25mg and Y-27632 was delivered by gavage at 2 mg/kg to the heart recipient. Bone marrow derived macrophages were subjected to in vitro motility, pahogocytsis and matrix degradation assays and immunostaining. Results. We show that administration of the CTLA-4Ig, which disrupts CD28/B7 pathway required for naive T cell activation, prevents acute rejection of cardiac allograft, however, the heart transplants develop classical features of chronic rejection. Additional blockade of ROCK using Y-27632 inhibitor results in long-term heart allograft survival, and these hearts are fee from TV, which contrasts sharply to those treated with CTLA4-Ig alone. These data indicate the RhoA pathway controls key responses that are critically involved in transplant vasculopathy, and such responses are distinct from those in acute rejection and are independent of CD28 costimulation. Our study shows that the most abundant immune cells present in vascular lesions are macrophages and that RhoA pathway inhibitor disrupts actin related macrophage functions such as macrophage polarization, migration, phagocytosis, matrix degradation and iNOS production in vitro. In vivo in transplant recipients, RhoA pathway inhibitor markedly reduces vascular endothelial activation in the grafts, as measured by Erk phosphorylation. Conclusions. Our studies show that RhoA is a central regulator of cells involved in chronic inflammation in response to injury, which results in TV, and these responses become predominant when acute cellular rejection is inhibited. Because at present there is no available anti-chronic rejection therapy, our studies are pivotal for development of novel anti-chronic rejection therapies.

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