Lutgens Esther, Lievens Dirk, Beckers Linda, Donners Marjo, Daemen Mat
Department of Pathology, University of Maastricht, Cardiovascular Research Institute Maastricht, 6229 HX Maastricht, The Netherlands.
Trends Cardiovasc Med. 2007 May;17(4):118-23. doi: 10.1016/j.tcm.2007.02.004.
CD40-CD40 ligand (CD40L) interactions play a central role in the development and progression of atherosclerosis. In the late 1990s, we and others have shown that complete inhibition of the CD40L signaling pathway resulted in a decrease in atherosclerosis and in the induction of a stable atherosclerotic plaque phenotype. These stable plaques contained high amounts of collagen and vascular smooth muscle cells, whereas the amount of macrophages and T lymphocytes was low. Because clinical complications of atherosclerosis are mostly the result of plaque rupture, induction of plaque stability would significantly reduce the morbidity and mortality of atherosclerosis and thus validates inhibition of the CD40L system as a therapeutic target for atherosclerosis. However, long-term inhibition of this system probably compromises the immune system of the patient. Therefore, it is desirable to target either the downstream signaling modulators of the CD40-CD40L system that are associated with atherosclerosis, or target the CD40-CD40L system in a local, cell type-specific way. This is likely to induce plaque stabilization with limited systemic side effects, and a significant reduction of cardiovascular disease.
CD40与CD40配体（CD40L）的相互作用在动脉粥样硬化的发生和发展中起着核心作用。在20世纪90年代后期，我们和其他人已经表明，完全抑制CD40L信号通路会导致动脉粥样硬化减少，并诱导出稳定的动脉粥样硬化斑块表型。这些稳定的斑块含有大量的胶原蛋白和血管平滑肌细胞，而巨噬细胞和T淋巴细胞的数量则很低。由于动脉粥样硬化的临床并发症大多是斑块破裂的结果，诱导斑块稳定将显著降低动脉粥样硬化的发病率和死亡率，从而验证抑制CD40L系统作为动脉粥样硬化的治疗靶点。然而，长期抑制该系统可能会损害患者的免疫系统。因此，理想的做法是靶向与动脉粥样硬化相关的CD40 - CD40L系统的下游信号调节剂，或以局部、细胞类型特异性的方式靶向CD40 - CD40L系统。这可能会在全身副作用有限的情况下诱导斑块稳定，并显著降低心血管疾病的发生率。
