Abstract
AIMS: Patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT) are at a risk of developing graft-vs.-host disease (GvHD) and are afflicted with an increased incidence of cardiovascular events. Whether allo-HCT contributes to atherosclerosis progression has not been addressed experimentally. METHODS AND RESULTS: Here, we applied a novel minor histocompatibility antigen mismatch allo-HCT mouse model by transplanting C57BL/6 mice deficient for the LDL receptor (B6.Ldlr-/-) with bone marrow (BM) or BM and T cells (BMT) from BALB/b donors (BALB/b, H-2b → B6.Ldlr-/-, and H-2b), and feeding recipients a western diet. Mild clinical GvHD symptoms ensued with low disease activity in typical GvHD target organs. However, allogeneic BMT recipients developed increased atherosclerotic lesions compared with mice receiving BM only or syngeneic BMT recipients. Atherosclerotic lesions showed a heightened infiltration of effector CD8+ T cells in the aorta of BMT recipients. Furthermore, BMT recipients exhibited significantly higher serum cholesterol levels than BM-recipients. Notably, CD8+ T-cell depletion in B6.Ldlr-/- BMT recipients reduced atherosclerotic lesion formation and decreased cholesterol levels. CONCLUSION: These data may provide a novel mechanistic underpinning for the clinically observed increased incidence of cardiovascular disease in long-term allo-HCT survivors. Moreover, we have identified CD8+ T cells as potential targets for mitigating GvHD-induced atherosclerosis.