Cosimi A B, Conti D, Delmonico F L, Preffer F I, Wee S L, Rothlein R, Faanes R, Colvin R B
Transplantation Unit, Massachusetts General Hospital, Boston 02114.
J Immunol. 1990 Jun 15;144(12):4604-12.
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.
这些研究使用一种与猴细胞间黏附分子-1（CD54）反应的鼠IgG2a单克隆抗体（R6.5），来测试同种异体移植排斥反应是否能通过干扰白细胞黏附而被阻断。在16只食蟹猴肾移植受体中，预防性给予R6.5作为唯一的免疫抑制剂，持续12天（0.01至2毫克/千克/天）。14只移植技术成功的受体的存活时间显著延长（对照组为9.2±0.6天，实验组为24.2±2.4天；p<0.001）。细胞间黏附分子-1（CD54）（ICAM-1）在猴的肾脏和其他器官的血管内皮上表达，其模式与人类相似。在对照组的细胞排斥反应期间，ICAM-1在内皮细胞、浸润的单核白细胞和肾小管细胞上的表达增加。与对照组相比，在给予R6.5期间进行的活检显示T细胞浸润（CD2、CD8、CD4）减少，动脉内皮炎症减轻。除了被mIgG可变包被外，循环T细胞没有变化。在其他8只受体中的6只中，给予R6.5（0.5至2毫克/千克/天，持续10天）逆转了因环孢素减量至亚治疗水平而导致的先前存在的排斥反应。有反应的移植物显示水肿和出血减少，但浸润情况没有一致的变化。在首次给药后1小时，小鼠IgG主要沉积在移植物血管内皮上，炎症浸润没有任何变化。小鼠IgG也沉积在正常器官的内皮上，没有引发炎症反应，并在4天内从内皮清除。由于结合的主要部位是血管内皮，我们推测该抗体阻断了与血管上移植物ICAM-1分子的黏附。抗ICAM-1也与受体细胞结合，并可能干扰抗原呈递和/或T细胞相互作用。无论机制如何，这些研究表明抗ICAM-1抗体在体内抑制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。
