Huang E H, Gabler D M, Krecic M E, Gerber N, Ferguson R M, Orosz C G
Department of Surgery, Ohio State University College of Medicine, Columbus 43210.
Transplantation. 1994 Dec 15;58(11):1216-22.
The immunosuppressive agents used clinically to prevent allograft rejection exert their effects by interfering with antigen-dependent T cell activation, endothelial cell function, or both. Gallium nitrate (GN) is immunosuppressive both in vitro and in vivo, and has potential for clinical use in transplant recipients. Therefore, we analyzed the influence of GN on gonadal vein endothelial cell (GVEC) and T cell activation. GVEC were stimulated with IFN gamma or TNF alpha in the presence or absence of GN, and tested for changes in levels of MHC class I, MHC class II, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression. GN did not interfere with the baseline or cytokine-enhanced expression of these molecules. Rather, it increased the expression of intercellular adhesion molecule-1 on GVEC, and this effect was further augmented in the presence of IFN gamma. In contrast, GN inhibited T cell proliferation stimulated by allogeneic GVEC or allogeneic monocytes in a dose-dependent manner. In transwell experiments, GN blocked the induction of MHC class II expression on isolated GVEC caused by alloactivated T cells, but not by recombinant IFN gamma. This suggests that GN can interfere indirectly with inflammatory responses of endothelial cells by interfering with local T cell activation and lymphokine production. Once lymphokines are produced, GN does not interfere with their effects on endothelial cells. GN is thought to act through transferrin receptors, but GVEC, unlike T cells, do not increase their expression of transferrin receptors, after stimulation with cytokines. This may explain their relative lack of sensitivity to GN. In general, GN appears to stimulate endothelial cells but suppress T cells. This paradoxic effect suggests that therapy with GN may enhance T cell-independent inflammatory responses, such as cellular infiltration and repair of tissue damage, while suppressing T cell-dependent responses, such as T cell-mediated tissue destruction and allograft rejection.
临床上用于预防同种异体移植排斥反应的免疫抑制剂，通过干扰抗原依赖性T细胞活化、内皮细胞功能或两者来发挥作用。硝酸镓（GN）在体外和体内均具有免疫抑制作用，在移植受者中具有临床应用潜力。因此，我们分析了GN对性腺静脉内皮细胞（GVEC）和T细胞活化的影响。在存在或不存在GN的情况下，用γ干扰素或肿瘤坏死因子α刺激GVEC，并检测I类主要组织相容性复合体、II类主要组织相容性复合体、血管细胞黏附分子-1和细胞间黏附分子-1表达水平的变化。GN不干扰这些分子的基础表达或细胞因子增强的表达。相反，它增加了GVEC上细胞间黏附分子-1的表达，并且在γ干扰素存在的情况下这种作用进一步增强。相比之下，GN以剂量依赖性方式抑制同种异体GVEC或同种异体单核细胞刺激的T细胞增殖。在Transwell实验中，GN阻断了同种异体活化T细胞而非重组γ干扰素引起的分离GVEC上II类主要组织相容性复合体表达的诱导。这表明GN可通过干扰局部T细胞活化和淋巴因子产生来间接干扰内皮细胞的炎症反应。一旦产生淋巴因子，GN就不会干扰它们对内皮细胞的作用。GN被认为通过转铁蛋白受体起作用，但与T细胞不同，GVEC在细胞因子刺激后不会增加其转铁蛋白受体的表达。这可能解释了它们对GN相对缺乏敏感性。一般来说，GN似乎刺激内皮细胞但抑制T细胞。这种矛盾的作用表明，用GN治疗可能增强非T细胞依赖性炎症反应，如细胞浸润和组织损伤修复，同时抑制T细胞依赖性反应，如T细胞介导的组织破坏和同种异体移植排斥反应。
