Hancock W W, Adams D H, Wyner L R, Sayegh M H, Karnovsky M J
Department of Pathology and Immunology, Monash Medical School, Alfred Hospital, Prahran, Victoria, Australia.
Am J Pathol. 1994 Nov;145(5):1008-14.
Studies of T cell-deficient or immunosuppressed animals undergoing arterial endothelial denudation have yielded conflicting results as to the contribution of the immune system to neointimal vascular smooth muscle 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-Dawley rats. Immunohistological studies using monoclonal antibodies showed that the carotid luminal occlusion observed was associated with smooth muscle cell proliferation and neointimal accumulation of large numbers of CD4+, ED1+ mononuclear cells but no T cells. There was also wide-spread 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 monocyte/macrophage accumulation and cytokine expression was tested by daily intraperitoneal administration for 14 days of a rat CD4-specific monoclonal antibody, BWH-4 (500 micrograms/day). Morphometric analysis at day 14 showed that the intimal area of animals treated with CD4 monoclonal antibody comprised 7% +/- 4% of the arterial wall compared with 50% +/- 6% in control animals (n = 6/group, P < 0.001). In addition, immunohistological studies showed that CD4 monoclonal antibody treatment markedly reduced the intimal accumulation of mononuclear and smooth muscle cells and essentially abrogated expression of the cytokines PDGF-BB, TGF-beta, IL-1 beta, TNF-alpha, and IL-8, plus the anticoagulant molecule, protein S. Our results document the extensive expression in vivo of cytokines that in vitro promote vascular smooth muscle cell proliferation, and suggest that CD4+ mononuclear cells or their secreted products play a key role in the pathogenesis of intimal hyperplasia after endothelial injury. Furthermore, these observations may have clinical relevance in the development of novel strategies to prevent arteriosclerosis.
对动脉内皮剥脱的T细胞缺陷或免疫抑制动物的研究，在免疫系统对血管内膜血管平滑肌细胞积聚和增殖的作用方面得出了相互矛盾的结果。我们研究了与Sprague-Dawley大鼠颈动脉球囊血管成形术后14天出现的内膜增生相关的细胞类型和细胞因子表达。使用单克隆抗体的免疫组织学研究表明，观察到的颈动脉管腔闭塞与平滑肌细胞增殖以及大量CD4⁺、ED1⁺单核细胞的内膜积聚有关，但没有T细胞。炎症细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和IL-8也有广泛染色，以及强效平滑肌有丝分裂原血小板衍生生长因子（PDGF）、转化生长因子-β（TGF-β）和蛋白S的密集表达。通过每天腹腔注射大鼠CD4特异性单克隆抗体BWH-4（500微克/天），持续14天，来测试平滑肌细胞增殖与单核细胞/巨噬细胞积聚及细胞因子表达之间的关系。第14天的形态计量分析表明，用CD4单克隆抗体治疗的动物内膜面积占动脉壁的7%±4%，而对照动物为50%±6%（每组n = 6，P < 0.001）。此外，免疫组织学研究表明，CD4单克隆抗体治疗显著减少了单核细胞和平滑肌细胞的内膜积聚，并基本消除了细胞因子PDGF-BB、TGF-β、IL-1β、TNF-α和IL-8以及抗凝血分子蛋白S的表达。我们的结果证明了在体外促进血管平滑肌细胞增殖的细胞因子在体内的广泛表达，并表明CD4⁺单核细胞或其分泌产物在内皮损伤后内膜增生的发病机制中起关键作用。此外，这些观察结果可能在预防动脉硬化新策略的开发中具有临床意义。
