Coito A J, Korom S, Graser E, Volk H D, Van De Water L, Kupiec-Weglinski J W
Harvard Medical School, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Transplantation. 1998 Mar 15;65(5):699-706. doi: 10.1097/00007890-199803150-00017.
Allograft rejection is associated with infiltration of inflammatory cells and local deposition of fibronectin (FN). This study was carried out to examine the hypothesis that peptides known to specifically block adhesive interactions between the connecting segment-1 (CS1)-binding domain of FN and alpha4beta1 integrin on circulating cells may interfere with the immune cascade, which would lead to acute rejection in transplant recipients.
Cardiac allografts from Lewis x Brown Norway F1 hybrids were rejected in 7+/-1 days in Lewis rats. Treatment with bioactive CS1 peptides (4 mg/kg/day i.v. for 7 days) abrogated acute rejection and prolonged cardiac allograft survival to 13+/-1 days (P<0.001). This effect correlated with decreased expression of total fibronectin and cell adhesion molecules, such as alpha4beta1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, as well as reduced infiltration by CD4+ and CD8+ T cells at the graft site. Treatment with CS1 peptides decreased alloantigen activation, as evidenced by decreased intragraft infiltration by CD25+ cells, and diminished expression of mRNA coding for Th1 (interleukin [IL]-2, interferon-gamma)- and Th2 (IL-4, IL-5, IL-6)-type cytokines. CS1-mediated immunosuppressive effects could be reversed and acute rejection recreated after adjunctive treatment of rats with recombinant IL-2.
Our data are consistent with the model in which in vivo interaction between the alpha4beta1 integrin receptor and the cell-associated CS1 motif of FN is critical for rejection cascade. The novel therapeutic approach of selectively blocking the alpha4beta1-FN activation pathway with CS1 peptides prevents acute allograft rejection by inhibiting expansion of antigen-specific T cells and inducing a transient state of cytokine-responsive anergy in the residual T-cell population.
同种异体移植排斥反应与炎症细胞浸润及纤连蛋白（FN）的局部沉积有关。本研究旨在检验以下假设：已知能特异性阻断FN连接段1（CS1）结合域与循环细胞上α4β1整合素之间黏附相互作用的肽，可能会干扰免疫级联反应，进而导致移植受者发生急性排斥反应。
Lewis大鼠在7±1天内排斥来自Lewis×Brown Norway F1杂交种的心脏异体移植物。用生物活性CS1肽（静脉注射4mg/kg/天，共7天）治疗可消除急性排斥反应，并将心脏异体移植物存活时间延长至13±1天（P<0.001）。这种效应与总纤连蛋白和细胞黏附分子（如α4β1、血管细胞黏附分子-1、细胞间黏附分子-1）表达降低以及移植部位CD4+和CD8+T细胞浸润减少相关。CS1肽治疗可降低同种异体抗原激活，这表现为移植内CD25+细胞浸润减少以及编码Th1（白细胞介素[IL]-2、干扰素-γ）型和Th2（IL-4、IL-5、IL-6）型细胞因子的mRNA表达降低。在用重组IL-2辅助治疗大鼠后，CS1介导的免疫抑制作用可被逆转并重新引发急性排斥反应。
我们的数据与以下模型一致，即α4β1整合素受体与细胞相关的FN的CS1基序之间的体内相互作用对排斥级联反应至关重要。用CS1肽选择性阻断α4β1-FN激活途径的新型治疗方法，通过抑制抗原特异性T细胞的扩增并在残余T细胞群体中诱导细胞因子反应性无反应的短暂状态，预防急性异体移植排斥反应。
