In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.
In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.
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DOI：
10.4049/jimmunol.144.12.4604
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发表时间：
1990-06
影响因子：
4.4
通讯作者：
Cosimi Ab;D. Conti;F. Delmonico;FredericI. Preffer;Wee Sl;R. Rothlein;R. Faanes;R. Colvin
中科院分区：
文献类型：
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作者：
Cosimi Ab;D. Conti;F. Delmonico;FredericI. Preffer;Wee Sl;R. Rothlein;R. Faanes;R. Colvin
这些研究使用与猴ICAM-1（CD 54）反应的鼠IgG 2a mAb（R6.5）检测是否可以通过干扰白细胞粘附来阻断同种异体移植物排斥反应。在16只食蟹猴肾移植受者中，R6.5作为唯一的免疫抑制剂连续给药12天（0.01至2 mg/kg/天）。14例移植技术成功的受者的生存期显著延长（24.2 +/- 2.4 vs 9.2 +/- 0.6天，对照组; p <0.001）。细胞间粘附分子-1（CD 54）（ICAM-1）在猴肾脏和其他器官的血管内皮上以与人类相似的模式表达。在对照组的细胞排斥反应中，内皮细胞、浸润的单核白细胞和肾小管细胞上ICAM-1的表达增加。与对照组相比，R6.5给药期间的活检显示T细胞浸润（CD 2、CD 8、CD 4）减少，动脉内皮炎症减少。循环T细胞中没有发生变化，除了可变的mIgG包被。在其他8名受体中的6名中，R6.5给药（0.5至2 mg/kg/天，持续10天）逆转了由于环孢菌素逐渐减少至亚治疗水平而导致的预先存在的排斥反应。反应移植物显示水肿和出血减少，但浸润没有一致的变化。在第一次给药后1小时，小鼠IgG主要沉积在移植物血管内皮上，而炎性浸润没有任何变化。小鼠IgG也沉积在正常器官的内皮上而不引起炎症反应，并在4天内从内皮上清除。由于结合的主要部位是血管内皮，我们假设抗体阻断了与血管上移植物ICAM-1分子的粘附。抗ICAM-1还结合受体细胞，并可能干扰Ag呈递和/或T细胞相互作用。无论机制如何，这些研究表明抗ICAM-1抗体抑制体内T细胞介导的损伤，并且ICAM-1是同种异体移植排斥发病机制中的关键分子。
These studies test whether allograft rejection can be blocked by interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5) reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft recipients, R6.5 was administered prophylactically as the sole immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14 recipients with technically successful grafts was significantly prolonged (24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001). Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular endothelium in the kidney and other organs in the monkey in a pattern similar to that in humans. During cellular rejection in controls, ICAM-1 expression increased on endothelial cells, infiltrating mononuclear leukocytes and tubular cells. Biopsies during R6.5 administration showed decreased T cell infiltration (CD2, CD8, CD4) compared with controls and decreased arterial endothelial inflammation. No changes occurred in circulating T cells, aside from variable coating with mIgG. In six of eight other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days) reversed preexisting rejection that resulted from taper of Cyclosporine to subtherapeutic levels. Responding grafts showed decreased edema and hemorrhage but no consistent change in the infiltrate. At 1 h after the first dose, mouse IgG deposited primarily on the graft vascular endothelium without any change in the inflammatory infiltrate. Mouse IgG also deposited on the endothelium of normal organs without eliciting an inflammatory response and was cleared from the endothelium within 4 days. Inasmuch as the principal site of binding was the vascular endothelium, we hypothesize that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels. Anti-ICAM-1 also binds to recipient cells and may interfere with Ag presentation and/or T cell interactions. Whatever the mechanism(s), these studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis of allograft rejection.