Abstract 155: Sustained CD4+ T-Cell Activation Promotes Transplant-Associated Recipient Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in transplant patients. The mechanisms underlying increased recipient CVD are poorly understood. We have established an animal model of transplant-associated recipient CVD by combining murine models of atherosclerosis (apolipoprotein E-deficient recipients, ApoE -/- ) and of transplant rejection (heterotopic cardiac transplantation). Mice were placed on a normal chow diet for 3 months after transplantation and then analyzed. ApoE -/- recipients of rejecting allografts developed more severe aortic atherosclerosis compared to syngeneic controls, most strikingly across a major histocompatibility complex (MHC) class II antigen barrier (Fig. A). Atherosclerotic lesions were associated with increased CD4 + T cell infiltration and sustained CD4 + T cell activation as assessed by flow cytometry. Total cholesterol and triglyceride levels were unchanged. Cardiac function and aortic distention by echocardiography demonstrated significant impairment in recipients of MHC class II mismatched grafts (Fig. B). In addition, quantitative assessment of proinflammatory cytokines demonstrated significantly elevated plasma levels of interferon (IFN)-γ, the signature Th1 cytokine, as well as IFN-γ inducer cytokine IL-12 in mice with MHC class II mismatched grafts. Our study provides an experimental model of transplant-associated recipient CVD, reveals the critical role of sustained CD4 + T cell activation by donor-recipient immunological crosstalk, and has the potential for identifying novel therapeutic interventions for transplant-associated recipient CVD.