Enhanced development of atherosclerosis in cholesterol-fed rabbits by suppression of cell-mediated immunity.

Abstract

T lymphocytes are present in atherosclerotic lesions, but the role of this cell type in the disease process has not been determined. To determine whether cell-mediated immunity influences atherogenesis, New Zealand White rabbits fed a cholesterol-supplemented diet (0.5% wt/wt) were treated with cyclosporin A (n = 20) or vehicle alone (n = 16) for 12 wk. The dose of cyclosporin A was adjusted so that a blood concentration between 100 and 200 ng/ml was maintained to achieve a selective action T-lymphocytes. Effectiveness of immunosuppression in cyclosporin A-treated rabbits was confirmed by allogeneic skin graft survival. Cyclosporin A administration did not affect total plasma lipid concentrations, body weight, or renal function. Percentage of aortic intimal area covered with atherosclerotic lesions was increased significantly by immunosuppression in both the arch region (75 +/- 3% [mean +/- SEM] compared with 60 +/- 5% in controls; P < 0.01) and the thoracic region (47 +/- 7% vs 27 +/- 6%; P = 0.04). Enhanced atherogenesis was not associated with diminished numbers of T lymphocytes in lesions, changes in T lymphocyte subtype, or any discernible change in cellular composition. Humoral immune responses to oxidized LDL were similar in the two groups: serum titres of autoantibodies against malondialdehyde-modified LDL were equivalent. These data demonstrate that cyclosporin A-induced suppression of cell-mediated immunity increased the development of macrophage-rich atherosclerotic lesions in cholesterol-fed rabbits.