CD4(-CELLS INDUCE CYTOKINE EXPRESSION, VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION, AND ARTERIAL-OCCLUSION AFTER ENDOTHELIAL INJURY() MONONUCLEAR)

Studies of T cell-deficient or immunosuppressed animals undergoing art erial endothelial denudation have yielded conflicting results as to th e contribution of the immune system to neointimal vascular smooth musc le cell accumulation and proliferation We investigated the cell types and cytokine expression associated with intimal hyperplasia occurring 14 days after balloon angioplasty of the carotid artery in Sprague-Daw ley mts. Immunohistological studies using monoclonal antibodies showed that the carotid luminal occlusion observed was associated with smoot h muscle cell proliferation and neointimal accumulation of large numbe rs of CD4(+), ED1(+) mononuclear cells but no T cells. There was also widespread staining for the inflammatory cytokine interleukin-1B (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and IL-8, as well as dense expression of the potent smooth muscle mitogens platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and protein S. The relationship of smooth muscle cell proliferation to mo nocyte/macrophage accumulation and cytokine expression was tested by d aily intraperitoneal administration for 14 days of a rat CD4-specific monoclonal antibody, BWH-4 (500 mu g/day). Morphometric analysis at da y 14 showed that the intimal area of animals treated with CD4 monoclon al antibody comprised 7% +/- 4% of the arterial wall compared with 50% +/- 6% in control animals (n = 6/group, P < 0.001). In addition, immu nohistological studies showed that CD4 monoclonal antibody treatment m arkedly reduced the intimal accumulation of mononuclear and smooth mus cle cells and essentially abrogated expression of the cytokines PDGF-B B, TGF-beta, IL-1 beta, TNF-alpha, and IL-8, plus the anticoagulant mo lecule, protein S. Our results document the extensive expression in vi vo of cytokines that in vitro promote vascular smooth muscle cell prol iferation, and suggest that CD4(+) mononuclear cells or their secreted products play a key role in the pathogenesis of intimal hyperplasia a fter endothelial injury. Furthermore, these observations may have clin ical relevance in the development of novel strategies to prevent arter iosclerosis.