Korom S, Hancock W W, Coito A J, Kupiec-Weglinski J W
Harvard Medical School, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Transplantation. 1998 Mar 27;65(6):854-9. doi: 10.1097/00007890-199803270-00014.
Chronic rejection remains the leading obstacle to long-term allograft survival. We have shown that treatment of sensitized rats with rapamycin (RPM) does not prevent progressive chronic-type cardiac allograft failure. Having documented the role of fibronectin (FN) in the allograft rejection cascade, we hypothesized that treatment with synthetic peptides that specifically block adhesive interactions between the connecting segment-1 (CS1)-binding domain of FN and alpha4beta1 integrin on circulating cells may prevent the development of chronic rejection in transplant recipients.
Lewis rats were sensitized with Brown Norway skin grafts (day -7), followed by transplantation of LBNF1 hearts (day 0). Experimental animals were treated with RPM (day -7 to -1; 0.25 mg/kg/day i.p.), or RPM + CS1 peptides (day +7 to +13; 4 mg/kg/day i.v.), and euthanized at day 60. Unlike cardiac allografts in rats undergoing RPM monotherapy, those after adjunctive CS1 peptides had well preserved myocardial architecture and were free of arteriosclerotic lesions. Moreover, reverse transcription-polymerase chain reaction-based intragraft expression of transcripts for CD3, interferon-gamma, interleukin-12, monocyte chemoattractant protein-1, and transforming growth factor-beta were diminished in the CS1 group when compared with levels in the RPM group. The corresponding expression of cytokine proteins, as determined by immunoperoxidase labeling, was also depressed and correlated with decreased infiltration by T cells and macrophages.
CS1 peptide-facilitated blockage of alpha4beta1-FN interactions prevents the development of chronic rejection and depresses the expression of key T cell- and macrophage-associated cytokines/chemoattractants. Hence, local synthesis of FN is an ongoing feature of, and adhesive FN-alpha4beta1 associations are critical for, the development of chronic transplant rejection.
慢性排斥反应仍然是同种异体移植物长期存活的主要障碍。我们已经表明，用雷帕霉素（RPM）治疗致敏大鼠并不能预防进行性慢性型心脏同种异体移植失败。在记录了纤连蛋白（FN）在同种异体移植排斥反应级联中的作用后，我们推测，用特异性阻断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合成肽进行治疗，可能预防移植受者慢性排斥反应的发生。
用棕色挪威大鼠皮肤移植物致敏Lewis大鼠（第-7天），随后移植LBNF1心脏（第0天）。实验动物接受RPM治疗（第-7天至-1天；腹腔注射0.25 mg/kg/天），或RPM + CS1肽治疗（第+7天至+13天；静脉注射4 mg/kg/天），并在第60天安乐死。与接受RPM单一疗法的大鼠心脏同种异体移植不同，辅助CS1肽治疗后的移植心脏心肌结构保存良好，无动脉硬化病变。此外，与RPM组相比，CS1组基于逆转录-聚合酶链反应的移植物内CD3、干扰素-γ、白细胞介素-12、单核细胞趋化蛋白-1和转化生长因子-β转录本的表达减少。通过免疫过氧化物酶标记测定的细胞因子蛋白的相应表达也降低，并且与T细胞和巨噬细胞浸润减少相关。
CS1肽促进的α4β1-FN相互作用阻断可预防慢性排斥反应的发生，并抑制关键的T细胞和巨噬细胞相关细胞因子/趋化因子的表达。因此，FN的局部合成是慢性移植排斥反应发生过程中的一个持续特征，而黏附性FN-α4β1关联对其发生至关重要。
