Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany Division of Intestinal Transplantation, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA.
Am J Transplant. 2010 Nov;10(11):2431-41. doi: 10.1111/j.1600-6143.2010.03279.x.
As we have shown in the past, acute rejection-related TNF-α upregulation in resident macrophages in the tunica muscularis after small bowel transplantation (SBTx) results in local amplification of inflammation, decisively contributing to graft dysmotility. Therefore, the aim of this study is to investigate the effectiveness of the chimeric-monoclonal-anti-TNF-α antibody infliximab as perioperative single shot treatment addressing inflammatory processes during acute rejection early after transplantation. Orthotopic, isogenic and allogenic SBTx was performed in rats (BN-Lewis/BN-BN) with infliximab treatment. Vehicle and IV-immunoglobulin-treated animals served as controls. Animals were sacrificed after 24 and 168 h. Leukocyte infiltration was investigated in muscularis whole mounts by immunohistochemistry, mediator mRNA expression by Real-Time-RT-PCR, apoptosis by TUNEL and smooth muscle contractility in a standard organ bath. Both, infliximab and Sandoglobulin® revealed antiinflammatory effects. Infliximab resulted in significantly less leukocyte infiltration compared to allogenic controls and IV-immunoglobulin, which was accompanied by lower gene expression of MCP-1 (24 h), IFN-γ (168 h) and infiltration of CD8-positive cells. Smooth muscle contractility improved significantly after 24 h compared to all controls in infliximab treated animals accompanied by lower iNOS expression. Perioperative treatment with infliximab is a possible pharmaceutical approach to overcome graft dysmotility early after SBTx.
如我们之前所示，小肠移植（SBTx）后，固有巨噬细胞中与急性排斥反应相关的 TNF-α 上调导致了肌层局部炎症放大，这对移植物运动障碍有决定性的影响。因此，本研究旨在探讨嵌合型抗 TNF-α 单克隆抗体英夫利昔单抗作为围手术期单次注射治疗，对移植后早期急性排斥反应期间炎症过程的有效性。在大鼠（BN-Lewis/BN-BN）中进行了原位、同基因和异基因 SBTx，并进行英夫利昔单抗治疗。载体和 IV 免疫球蛋白治疗的动物作为对照。动物在 24 和 168 小时后被处死。通过免疫组织化学研究肌层全层切片中的白细胞浸润，通过 Real-Time-RT-PCR 研究介质 mRNA 表达，通过 TUNEL 研究细胞凋亡，通过标准器官浴研究平滑肌收缩性。英夫利昔单抗和 Sandoglobulin®均显示出抗炎作用。与同种异体对照组和 IV 免疫球蛋白相比，英夫利昔单抗导致的白细胞浸润明显减少，同时 MCP-1（24 小时）、IFN-γ（168 小时）的基因表达和 CD8 阳性细胞浸润也较低。与所有对照组相比，英夫利昔单抗治疗动物的平滑肌收缩性在 24 小时后明显改善，同时 iNOS 表达降低。围手术期使用英夫利昔单抗是克服 SBTx 后早期移植物运动障碍的一种可行的药物治疗方法。
