TRIPLE-DRUG IMMUNOSUPPRESSION SIGNIFICANTLY REDUCES AORTIC ALLOGRAFT ARTERIOSCLEROSIS IN THE RAT

We evaluated the effect of triple drug immunosuppression (cyclosporine A 10 mg . kg(-1). d(-1), methylprednisolone 0.5 mg . k(-1). d(-1), an d azathioprine 2 mg . kg(-1). d(-1)) on the development of allograft a rteriosclerosis (chronic rejection). The recipients of rat aortic allo grafts from the DA (AG-B4, RT1(a)) to the WF (AG-BZ, RT1(u)) strain we re either treated with triple drug immunosuppression (n=23) or left un treated (n=23) and used as controls. The grafts were removed 7, 14, 30 , 90, and 180 days after transplantation, and vascular wall changes we re evaluated by quantitative histology, [H-3]thymidine autoradiography , and immunohistochemistry. Nonimmunosuppressed aortic allografts deve loped progressive arteriosclerotic alterations 1 to 6 months after tra nsplantation that were virtually identical to those observed during ch ronic rejection in human cardiac allografts. Linear regression analysi s revealed that triple drug immunosuppression with clinically relevant dosages of drugs significantly reduced intimal thickening (r=.69 vers us r=.88, P<.05). Concomitantly, there was a marked reduction in the n umber of inflammatory cells (P<.01) and their rate of proliferation (P <.025) in the allograft adventitia during the period of acute inflamma tion (30 days after transplantation). Immunohistochemistry revealed th at the number of helper T cells (W3/25) and monocyte/macrophages (OX42 ) but not cytotoxic T cells (OX8) or natural killer cells (3.2.3) was significantly (P<.05) reduced. The number of adventitial cells express ing interleukin-2 receptor (CD25) (P<.05), MHC class II (OX6) (P<.05), and leukocyte function-associated antigen-1 alpha-chain (CD11a) (P<.0 25) was also significantly reduced at 30 days. Triple drug immunosuppr ession downregulated the induction of MHC class II and intercellular a dhesion molecule-1 on the graft endothelium but had no significant eff ect on the number of subendothelial inflammatory cells. In addition, [ H-3]thymidine autoradiography demonstrated that triple drug immunosupp ression significantly reduced the rate of cell proliferation in the me dia, composed of smooth muscle cells, 30 and 90 days after transplanta tion. Thus, triple drug immunosuppression efficiently reduced the deve lopment of allograft arteriosclerosis by downregulating the inflammato ry response and the level of immune activation in the allograft advent itia during the acute rejection period, resulting in diminished intima l thickening of the graft in the long run. These results support the c oncept that allograft arteriosclerosis is due to or al least initialed by immune injury of the graft.