Tung Thomas H H, Mackinnon Susan E, Mohanakumar T
Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Transplantation. 2003 Mar 15;75(5):644-50. doi: 10.1097/01.TP.0000053756.90975.8E.
Costimulation blockade has been shown to be effective in achieving donor-specific immune unresponsiveness in models of organ transplantation. This study represents the first application of blockade of the CD40 costimulatory pathway to a murine model of limb allotransplantation.
Eighteen Balb/c mice (H-2K(d)) were randomized to four groups. The control group (n=5) received syngeneic limb transplants from Balb/c donors. The experimental groups were recipients of limb allografts from C57Bl/6 mice (H-2K(b)) and received either no treatment (n=5) or treatment with MR1 (hamster antimouse CD40 ligand monoclonal antibody) 500 microg intraperitoneally (IP) on days 0, 2, 4, 6, 14, 28, and 60 (n=5). A fourth group received myocutaneous allografts from C57Bl/6 donors and the same treatment with MR1 (n=5).
Untreated limb allografts were rejected at a mean of 9.6+/-1.1 days postoperatively. MR1-treated limb allografts underwent rejection of the skin component at a mean of 75+/-25 days whereas the musculoskeletal component survived to a mean of 222+/-84 days with two allografts surviving more than 10 months (P<0.001). The MR1-treated myocutaneous allografts were rejected after 16.2+/-2 days. All groups demonstrated acute rejection on histology except the treated limb allograft group, which was more suggestive of a chronic process. No chimerism was detected in this group by flow cytometry.
CD40 costimulatory blockade significantly prolonged limb-allograft survival, and the bone-marrow component may have played an important role. Tolerance was not achieved, and histologic evaluation suggested chronic rejection as a possible cause of allograft loss.
在器官移植模型中，共刺激阻断已被证明可有效实现供体特异性免疫无反应。本研究首次将CD40共刺激通路阻断应用于小鼠肢体同种异体移植模型。
将18只Balb/c小鼠（H-2K(d)）随机分为四组。对照组（n = 5）接受来自Balb/c供体的同基因肢体移植。实验组接受来自C57Bl/6小鼠（H-2K(b)）的肢体同种异体移植，其中一组不接受治疗（n = 5），另一组在第0、2、4、6、14、28和60天腹腔内注射500微克MR1（仓鼠抗小鼠CD40配体单克隆抗体）（n = 5）。第四组接受来自C57Bl/6供体的肌皮同种异体移植，并接受相同的MR1治疗（n = 5）。
未治疗的肢体同种异体移植在术后平均9.6±1.1天被排斥。接受MR1治疗的肢体同种异体移植的皮肤成分平均在75±25天被排斥，而肌肉骨骼成分平均存活至222±84天，有两个同种异体移植存活超过10个月（P<0.001）。接受MR1治疗的肌皮同种异体移植在16.2±2天后被排斥。除接受治疗的肢体同种异体移植组外，所有组在组织学上均表现为急性排斥，该组更提示为慢性过程。通过流式细胞术在该组中未检测到嵌合体。
CD40共刺激阻断显著延长了肢体同种异体移植的存活时间，骨髓成分可能起到了重要作用。未实现耐受，组织学评估提示慢性排斥可能是同种异体移植丢失的原因。
