Miwa S, Isobe M, Suzuki J, Makuuchi M, Miyasaka M, Yamazaki S, Kawasaki S
First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
Surgery. 1997 Jun;121(6):681-9. doi: 10.1016/s0039-6060(97)90057-x.
The interaction between intercellular adhesion molecule-1 (ICAM-1) and its ligand, leukocyte function associated antigen-1 (LFA-1), is especially relevant in allograft rejection. We have previously shown that the simultaneous blockade of ICAM-1 and LFA-1 by monoclonal antibodies (mAbs) results in specific immunologic tolerance to cardiac allograft in a mouse model.
We evaluated the roles of these adhesion molecules in xenograft rejection by using a rat-to-mouse concordant xenograft model to identify critical molecules for immunosuppression.
Lewis rat hearts transplanted into C3H/He mice were rejected within 5 to 7 days without treatment. A significant prolongation of xenograft survival (mean survival time, 11.6 days) was observed after treatment with anti-rat ICAM-1 and anti-mouse LFA-1 mAbs, when compared with nontreated mice or mice treated with different combinations of mAbs. Graft survival was prolonged in mice treated with FK506 (1 mg/kg/day), anti-rat ICAM-1, and anti-mouse LFA-1 mAbs (mean survival time, 22.2 days), whereas the same dose of FK506 alone was not effective. The mixed lymphocyte reaction showed that a combination of mAbs against mouse LFA-1-rat ICAM-1 and rat LFA-1-mouse ICAM-1 significantly inhibited the proliferation of mouse responders to rat stimulators and rat responders to mouse stimulators, respectively. Infiltration of mouse CD4 positive, mouse CD8 positive, and mouse LFA-1 positive cells, as well as dense deposition of mouse immunoglobulin G (IgG), IgM, and up-regulation of rat ICAM-1, on the graft endothelial cells were demonstrated by immunopathologic analysis of the rejected hearts. Flow cytometric analysis with rat spleen cells demonstrated the presence of xenoreactive antibodies (mouse IgG and IgM) in the recipient's serum. This xenoreactive antibody production was delayed but not inhibited by treatment of the recipients with anti-rat ICAM-1 and anti-mouse LFA-1.
Blockade of the donor side ICAM-1 and the recipient side LFA-1 is critical for immunosuppression with anti-ICAM-1-LFA-1 treatment. Humoral factors may be responsible for xenograft rejection that occurs even after inhibition of the cell-mediated immune response by anti-ICAM-1 and anti-LFA-1 mAbs.
细胞间黏附分子-1（ICAM-1）与其配体白细胞功能相关抗原-1（LFA-1）之间的相互作用在同种异体移植排斥反应中尤为重要。我们之前已经表明，单克隆抗体（mAb）同时阻断ICAM-1和LFA-1可在小鼠模型中诱导对心脏同种异体移植的特异性免疫耐受。
我们通过使用大鼠到小鼠的协调性异种移植模型来评估这些黏附分子在异种移植排斥反应中的作用，以确定免疫抑制的关键分子。
未治疗的情况下，Lewis大鼠心脏移植到C3H/He小鼠体内会在5至7天内被排斥。与未治疗的小鼠或用不同mAb组合治疗的小鼠相比，用抗大鼠ICAM-1和抗小鼠LFA-1 mAb治疗后，异种移植物存活时间显著延长（平均存活时间为11.6天）。用FK506（1毫克/千克/天）、抗大鼠ICAM-1和抗小鼠LFA-1 mAb治疗的小鼠移植物存活时间延长（平均存活时间为22.2天），而单独使用相同剂量的FK506则无效。混合淋巴细胞反应表明，针对小鼠LFA-1 - 大鼠ICAM-1和大鼠LFA-1 - 小鼠ICAM-1的mAb组合分别显著抑制了小鼠应答细胞对大鼠刺激细胞以及大鼠应答细胞对小鼠刺激细胞的增殖。对排斥心脏的免疫病理分析显示，移植心脏的内皮细胞上有小鼠CD4阳性、小鼠CD8阳性和小鼠LFA-1阳性细胞浸润，以及小鼠免疫球蛋白G（IgG）、IgM的密集沉积和大鼠ICAM-1的上调。用大鼠脾细胞进行的流式细胞术分析表明受体血清中存在异种反应性抗体（小鼠IgG和IgM）。用抗大鼠ICAM-1和抗小鼠LFA-1治疗受体可延迟但不能抑制这种异种反应性抗体的产生。
阻断供体侧ICAM-1和受体侧LFA-1对于抗ICAM-1 - LFA-1治疗的免疫抑制至关重要。体液因子可能是导致即使在抗ICAM-1和抗LFA-1 mAb抑制细胞介导的免疫反应后仍发生异种移植排斥反应的原因。
