Department of General Surgery, the First Affiliated Hospital of Suzhou University, Suzhou, Jiangsu 215006, China.
Chin Med J (Engl). 2010 Jan 20;123(2):212-5.
Blocking the 4-1BB/4-1BB ligand (4-1BBL) signal may modulate the secretion of Th1/Th2 cytokines and prolong the survival of the grafts, which play a key role in organ transplantation tolerance. The aim of this study was to investigate the role of blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody (mAB) in acute rejection of rat orthotopic liver transplantation.
The orthotopic liver transplantation model was set up, while male Lewis rats were used as liver donors and Brown-Norway rats as recipients. The recipient rats were intravenously injected with anti 4-1BBL mAB or isotype control antibody. Groups were monitored for graft survival after transplantation. Plasma chemistry, including aspartate transaminase (AST), alanine aminotransferase (ALT), and bilirubin (BIL), was assayed. The concentrations of interleukin (IL)-2, IL-10 and interferon (IFN)-gamma in plasma were also measured by enzyme-linked immunosorbent assay. Allograft histology images were collected under light microscope and electron microscope.
Isotype antibody treated recipients exhibited elevated plasma levels of liver injury markers including AST, ALT and BIL, progressive portal and venous inflammation and cellular infiltration of the liver allografts, and a mean graft survival time (MST) of 10.9 days. Administration of anti 4-1BBL mAB resulted in a decrease in plasma levels of liver injury markers and the concentrations of IL-2, IL-10 and IFN-gamma. The histological grade of rejection on day 7 decreased and MST (17.3 days) increased substantially.
These results demonstrate that attenuation of acute rejection follows the blockade of the 4-1BB/4-1BBL co-stimulatory pathway with 4-1BBL monoclonal antibody and strongly suggest it is a promising strategy to prevent progression of graft rejection by suppressing T cell-mediated immunity.
阻断 4-1BB/4-1BB 配体（4-1BBL）信号可能调节 Th1/Th2 细胞因子的分泌并延长移植物的存活时间，这在器官移植耐受中起着关键作用。本研究旨在探讨用 4-1BBL 单克隆抗体（mAB）阻断 4-1BB/4-1BBL 共刺激途径在大鼠原位肝移植急性排斥反应中的作用。
建立大鼠原位肝移植模型，雄性 Lewis 大鼠作为供肝，Brown-Norway 大鼠作为受体。受体大鼠静脉注射抗 4-1BBL mAB 或同型对照抗体。移植后监测移植物存活情况。检测血浆化学物质，包括天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和胆红素（BIL）。酶联免疫吸附试验检测血浆中白细胞介素（IL）-2、IL-10 和干扰素（IFN）-γ的浓度。采集肝移植组织光镜和电镜图像。
同型抗体处理的受体大鼠表现出肝损伤标志物包括 AST、ALT 和 BIL 的血浆水平升高，门脉和静脉炎症以及肝移植物细胞浸润逐渐加重，平均移植物存活时间（MST）为 10.9 天。给予抗 4-1BBL mAB 可降低肝损伤标志物和 IL-2、IL-10 和 IFN-γ的浓度。第 7 天排斥反应的组织学分级降低，MST（17.3 天）显著增加。
这些结果表明，阻断 4-1BB/4-1BBL 共刺激途径可减轻急性排斥反应，强烈提示通过抑制 T 细胞介导的免疫来抑制移植物排斥反应的进展是一种很有前途的策略。
