Interferon-γ deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts

Abstract

We have hypothesized that T cell cytokines participate in the pathogenesis of graft arterial disease (GAD). This study tested the consequences of IFN-γ deficiency on arterial and parenchymal pathology in murine cardiac allografts. Hearts from C-H-2bm12KhEg (bm12, H-2bm12) were transplanted into C57/B6 (B6, H-2b), wild-type, or B6 IFN-γ-deficient (GKO) recipients after immunosuppression by treatment with anti-CD4 and anti- CD8 mAbs. In wild-type recipients, myocardial rejection peaked at 4 wk, (grade 2.1±0.3 out of 4, mean±SEM, n = 9), and by 8-12 wk evolved coronary arteriopathy. At 12 wk, the GAD score was 1.4±0.3, and the parenchymal rejection grade was 1.2±0.3 (n = 8). In GKO recipients of bm12 allografts, myocardial rejection persisted at 12 wk (grade 2.5±0.3, n = 6), but no GAD developed (score: 0.0±0.0, n = 6, P < 0.01 vs. wild-type). Mice treated with anti-IFN-γ, mAbs showed similar results. Isografts generally showed no arterial changes. In wild-type recipients, arterial and parenchymal cells showed increased MHC class II molecules, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 compared to normal or isografted hearts. The allografts in GKO recipients showed attenuated expression of these molecules (n = 6). Thus, development of GAD, but not parenchymal rejection, requires IFN-γ. Reduced expression of MHC antigens and leukocyte adhesion molecules may contribute to the lack of coronary arteriopathy in hearts allografted into GKO mice.