Yang H, Issekutz T B, Wright J R
Department of Pathology, Izaak Walton Killam Children's Hospital, Dalhousie University Faculty of Medicine, Halifax, Nova Scotia, Canada.
Transplantation. 1995 Jul 15;60(1):71-6. doi: 10.1097/00007890-199507150-00014.
In this study, we investigated the effects of treatment with monoclonal antibodies against the VLA-4 and LFA-1 adhesion molecules on rat islet allograft rejection. TA-2 and TA-3 are function-blocking mAb against rat VLA-4 and LFA-1, respectively. Lewis rats were made diabetic (plasma glucose levels > 22.2 mmol/L) with streptozotocin. One week later, 1500 freshly isolated Wistar Furth rat islets were transplanted under the left kidney capsule of each rat. Monoclonal antibodies were administered intravenously at a dosage of 2 mg on the day of islet transplantation and then intraperitoneally every second day for 3 weeks or until graft rejection. Plasma glucose levels were monitored at least 3 times a week and blood leukocyte counts were monitored every 4 days. Rejection was defined as 2 plasma glucose levels > 11.1 mmol/L. Mean graft survival times in untreated and control mAb-treated rats were 5.3 and 6.0 days, respectively. Treatment with anti-VLA-4 or anti-LFA-1 resulted in only modest prolongation of mean graft survival time (9.3 and 7.4 days, respectively). However, treatment with the combination of anti-VLA-4 plus anti-LFA-1 resulted in long-term (i.e., 60-day) graft survival in 5 of 7 rats. Graft nephrectomy and histology confirmed islet graft survival at 60 days. A second Wistar Furth rat islet graft under the opposite renal capsule after graft nephrectomy did not show full tolerance; however, the function of the second graft was significantly prolonged without any immunosuppression. Combined blockade of VLA-4 and LFA-1 also markedly prolonged islet graft survival when islets were transplanted via the portal vein. In conclusion, both VLA-4 and LFA-1 play a role in islet allograft rejection and blockade of both prevents or greatly delays graft rejection.
在本研究中，我们调查了用抗VLA-4和LFA-1黏附分子的单克隆抗体治疗对大鼠胰岛同种异体移植排斥反应的影响。TA-2和TA-3分别是针对大鼠VLA-4和LFA-1的功能阻断性单克隆抗体。用链脲佐菌素使Lewis大鼠患糖尿病（血糖水平>22.2 mmol/L）。一周后，将1500个新鲜分离的Wistar Furth大鼠胰岛移植到每只大鼠的左肾包膜下。在胰岛移植当天静脉注射单克隆抗体，剂量为2 mg，然后每隔一天腹腔注射一次，共3周或直至移植物排斥。每周至少监测3次血糖水平，每4天监测一次血液白细胞计数。排斥反应定义为两次血糖水平>11.1 mmol/L。未治疗和用对照单克隆抗体治疗的大鼠的平均移植物存活时间分别为5.3天和6.0天。用抗VLA-4或抗LFA-1治疗仅使平均移植物存活时间适度延长（分别为9.3天和7.4天）。然而，用抗VLA-4加抗LFA-1联合治疗使7只大鼠中的5只实现了长期（即60天）移植物存活。移植物肾切除术和组织学证实60天时胰岛移植物存活。移植物肾切除术后在对侧肾包膜下植入第二个Wistar Furth大鼠胰岛移植物未表现出完全耐受；然而，第二个移植物的功能在没有任何免疫抑制的情况下显著延长。当通过门静脉移植胰岛时，联合阻断VLA-4和LFA-1也显著延长了胰岛移植物存活时间。总之，VLA-4和LFA-1在胰岛同种异体移植排斥反应中均起作用，同时阻断两者可预防或大大延迟移植物排斥。
