Pathology and mechanisms of graft arterial disease. (A) A cross section of a normal muscular artery is shown. The thin intima includes the endothelial lining of the lumen and minimal subendothelial connective tissue. The media is demarcated by internal and external elastic lamina and includes vascular SMCs. The adventitia is a loose connective tissue sheath outside the media. There are few or no inflammatory cells in any of the layers. (B) In graft arteriosclerosis, inflammatory cells, including T cells and macrophages, infiltrate both the adventitia and the intima. Furthermore, SMCs derived from either the media or circulating host progenitors enter the intima and proliferate. This results in thickening of the lumen and eventual luminal narrowing. (C) A proposed mechanism of intimal SMC proliferation is shown, based on recent data from the Pober laboratory (12). IFN-γ is produced by alloreactive T cells within graft arterial walls. The IFN-γ blocks the expression of eNOS and enhances the expression of iNOS by the T cells themselves. Excess NO produced by the T cells may desensitize SMCs to the relaxation and antiproliferative effects of NO. Neutralization of IFN-γ blocks changes in eNOS and iNOS expression induced by alloreactve T cells, and a pharmacologic inhibitor of iNOS partially blocks development of intimal SMC accumulation.