Hadidi Sima, Chen Zhiqi, Phillips Jim, Yu Kai, Gorczynski Reginald M
Toronto General Hospital, Transplant Research Division, 200 Elizabeth Street, Toronto, M5G 2C4 Ontario, Canada.
Transplantation. 2002 Jun 15;73(11):1771-9. doi: 10.1097/00007890-200206150-00013.
Altered expression of murine MD-1, a molecule controlling expression of members of the interleukin (IL)-1 receptor family of signaling proteins, regulates antigen-presenting cell-induced alloreactions. We investigated the effect of treatment with antisense deoxyoligonucleotides or antibodies to MD-1 in vivo on allogeneic and xenogeneic skin graft survival and the immune responses in transplanted mice.
C3H mice received C57BL/6 or Lewis rat skin grafts, followed by i.v. injections of anti-MD-1 antibody or antisense oligonucleotides or control reagents at 48-hr intervals. Survival was monitored. In separate studies, mice were sacrificed at 5-day intervals. Serum was analyzed for circulating MD-1 antigen, and peritoneal cells for surface expression of MD-1. The proliferative and cytolytic response of lymphocytes harvested from treated animals and restimulated in vitro with allo- or xenogeneic cells, and the cytokines produced, was measured. Graft histology was assessed at 11 days after transplantation.
Treatment with anti-MD-1 oligonucleotides or antibodies suppressed rejection of both xeno- and allogeneic grafts, decreased induction of graft-specific cytotoxic T cells, increased production of type-2 cytokines (IL-4 and IL-10), and decreased production of type-1 cytokines (IL-2 and interferon-gamma). Serum levels of MD-1 were suppressed, as was expression of MD-1 on the surface of antigen-presenting cells. Grafts from MD-1-treated mice showed little lymphocyte infiltration, and no signs of graft necrosis.
Our data suggest a critical in vivo role for MD-1 expression in regulating graft rejection, as well as in the concomitant sensitization of T cells and their cytokine production profile, which parallels the rejection response.
小鼠MD-1是一种控制白细胞介素（IL）-1受体家族信号蛋白成员表达的分子，其表达改变可调节抗原呈递细胞诱导的同种异体反应。我们研究了体内用反义脱氧寡核苷酸或抗MD-1抗体治疗对异体和异种皮肤移植存活及移植小鼠免疫反应的影响。
C3H小鼠接受C57BL/6或Lewis大鼠皮肤移植，随后每隔48小时静脉注射抗MD-1抗体或反义寡核苷酸或对照试剂。监测移植皮肤的存活情况。在单独的研究中，每隔5天处死小鼠。分析血清中循环MD-1抗原，分析腹膜细胞表面MD-1的表达。测量从治疗动物收获并在体外与同种或异种细胞再刺激的淋巴细胞的增殖和细胞溶解反应，以及产生的细胞因子。在移植后11天评估移植组织学。
用抗MD-1寡核苷酸或抗体治疗可抑制异种和同种异体移植的排斥反应，减少移植特异性细胞毒性T细胞的诱导，增加2型细胞因子（IL-4和IL-10）的产生，减少1型细胞因子（IL-2和干扰素-γ）的产生。血清MD-1水平受到抑制，抗原呈递细胞表面MD-1的表达也受到抑制。来自MD-1治疗小鼠的移植组织显示淋巴细胞浸润很少，没有移植坏死的迹象。
