TNF-α blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation:: A novel anti-inflammatory mechanism of infliximab in Crohn's disease
TNF-α blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation:: A novel anti-inflammatory mechanism of infliximab in Crohn's disease
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DOI：
10.4049/jimmunol.176.4.2617
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发表时间：
2006-02-15
影响因子：
4.4
通讯作者：
Fiocchi, C
中科院分区：
文献类型：
--
作者：
Danese, S;Sans, M;Fiocchi, C
CD40/CID40配体(CD40L)通路参与了克罗恩病(CD)的发病过程。在患者循环中，可溶性CD40L(SCD40L)水平升高，表面CD40L在血小板和T细胞中增加，而在肠道中，CD40在微血管中过表达，CD40L在血小板和T细胞中过表达。英夫利昔单抗对CD的治疗作用归因于其全身性抗肿瘤坏死因子-α作用，但由于肿瘤坏死因子-α同时调节CD40和CD40L，我们研究英夫利昔单抗是否影响肠道中的CD40/CD40L途径。对18例CD患者在英夫利昔单抗治疗前后进行评估。用双抗体夹心法检测血浆sCD40L，用流式细胞仪检测血小板和外周血T细胞(PBT)CD40L表达。用免疫组织化学和流式细胞术检测人肠微血管内皮细胞(HIMEC)微血管CD40和VCAM-1的表达。在英夫利昔单抗存在和不存在的情况下进行细胞培养。英夫利昔单抗治疗可显著降低血浆sCD40L水平，清除粘膜微血管CD40和VCAM-1。在体外，英夫利昔单抗可抑制HIMEC诱导的CD40和VCAM-1的表达，并减少PBT，而不是血小板，表面CD40L的表达和sCD40L的释放。此外，英夫利昔单抗通过下调T细胞CD40L表达，促进T细胞凋亡，从而减少T细胞诱导的HIMEC中VCAM-I的表达。这些发现指出了英夫利昔单抗的一种新的作用机制，即破坏依赖CD40/CD40L的肠道微血管和T细胞之间的同源相互作用。因此，除了中和肿瘤坏死因子-α和诱导T细胞死亡外，英夫利昔单抗在CD中的治疗作用似乎也是通过抑制肠道血管炎症来实现的。
The CD40/CID40 ligand (CD40L) pathway is involved in Crohn's disease (CD) pathogenesis. In the patients' circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-alpha action, but because TNF-alpha modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Mlicrovascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immumohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-alpha-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-I expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-alpha and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.