Abstract 219: IFN-γ Plays an Essential Role in Accelerating Cardiovascular Disease of Recipients With MHC Class II-mismatched Allografts.

Abstract

Background: Organ transplant recipients die from cardiovascular disease (CVD) at a higher rate than the general population. Traditional treatment with statins to mitigate risk factors such as hyperlipidemia has had limited success. Using an animal model of graft-accelerated recipient CVD by combining murine models of atherosclerosis and heterotopic heart transplantation, we aim to better understand its pathogenesis and to explore more effective therapeutic strategies. Methods and Results: C57BL/6 (B6) ApoE-deficient recipient mice were heterotopically transplanted with MHC class II mismatched cardiac allografts from donor BM12 mice. Isograft controls were from donor B6 mice. IFN-γ neutralization antibody or isotype IgG was given subcutaneously at a dose of 250 μg per mouse 1 day prior to transplantation and thereafter 125 μg per mouse, 3 times per week for 12 weeks. Serum levels of cholesterol and triglyceride were measured by Amplex® Red Cholesterol Assay Kit and Triglyceride Determination Kit respectively. Inflammatory cytokines were assessed by both real-time PCR and flow cytometry. Native heart function of host mice was evaluated by echocardiography. Aortic atherosclerotic plaques in the host were examined by Oil Red O staining. MHC class II upregulation and neointimal formation in host coronary arteries were determined by immunofluorescence and EVG staining respectively. We found the levels of cholesterol and triglyceride were not changed by introducing allografts into host mice. However, a higher level of IFN-γ was produced by circulating and splenic CD4 T cells in hosts with allografts that was associated with de novo expression of endothelial MHC class II alloantigens in native coronary arteries. These phenomena were diminished by IFN-γ neutralization. Additionally, IFN-γ depletion reduced the local accumulation of IFN-γ and IP-10 mRNA in the native hearts and neointimal formation of coronary arteries in the hosts of allografts. Most importantly, IFN-γ neutralization prevented impaired cardiac function and increased aortic atherosclerotic burden in host mice with allografts. Conclusions: Our study reveals an essential role of IFN-γ in accelerating recipient CVD due to systemic inflammation from allograft rejection.