CYCLOSPORINE TREATMENT REDUCES EARLY ATHEROSCLEROSIS IN THE CHOLESTEROL-FED RABBIT

While T helper cell infiltration is an early event in the development of atherosclerosis in cholesterol-fed rabbits, their functional contribution to atherogenesis is not clear. To investigate their role, T cell activation was blocked with cyclosporine A (CsA) in New Zealand White (NZW) rabbits fed a 1% cholesterol diet. CsA was administered at a dose of 16 mg/kg body weight, intramuscularly every second day, resulting in circulating whole blood levels of 460 +/- 39 mu g/l. After 4 weeks on the cholesterol diet, untreated rabbits developed atherosclerotic plaques covering 74.4% +/- 3.5% of their aortic arch, 19.8% +/- 7.8% of their thoracic aorta and 19.8% +/- 6.2% of their abdominal aorta. T cells were observed in plaques of their aortic arches (CD5 positive, 11.1 +/- 7.3 cells/mm(2); CD4 positive, 9.9 +/- 4.9 cells/mm(2)) by immunofluorescence using monoclonal anti-rabbit CD5 and CD4 antibodies. Rabbits treated with CsA developed significantly less extensive plaques after 4 weeks (aortic arch 33.0% +/- 6.2%, P < 0.001; thoracic aorta 6.3% +/- 1.5%, P < 0.05; abdominal aorta 2.7% +/- 0.5%, P < 0.005) than untreated rabbits. No CD4 or CD5 positive cells were observed in their plaques. Treatment with CsA did not Effect the weight gain of rabbits or reduce their serum cholesterol levels. Circulating T cell numbers and subsets were unaffected. These studies suggest that inhibition of T cell activation prevents their localisation in plaques and reduces the extent of early lesions, suggesting a role for T cells in the initiation of atherosclerosis.