Tze W J, Tai J, Cheung S S
Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Diabetes Res Clin Pract. 1997 Sep;37(3):149-56. doi: 10.1016/s0168-8227(97)00068-5.
FK506 a new and potent immunosuppressive agent has been shown to be effective in prolonging pancreatic islet allograft survival. The present study was to determine its efficacy in prolonging pig islet xenotransplantation in two different strains of rat recipients. A total of two dosages of FK506 at 1 or 2 mg/kg per day for 2 weeks and then at weekly intervals were tested as monotherapy for their effect on the survival of renal subcapsular xenografts of purified or impure adult pig islets in inbred ACI and outbred Wistar rats. Histological assessment indicated that FK506 at 2 mg/kg per day significantly prolonged purified pig islet xenograft survival and to 7.5 months in two of three ACI recipients. Monotherapy with a lower dosage of FK506 or transplantation with impure pig islets resulted in increased graft survival time over controls, but less than that with the 2 mg/kg per day FK506. The viable pig islet xenografts showed a normal appearance and were readily identified by immunohistochemical staining for insulin and glucagon and further confirmed by immunohistochemical staining with anti-pig islet specific monoclonal antibody clone P44, developed in our laboratory. Mononuclear cell infiltration, mainly of the CD8-positive T-cell subset, increased with the duration of the graft in the recipient. By 7.5 months the majority of the xenografted islet cells were enclosed by the cellular infiltrate. The in vitro perfusion study of pig islets that had survived for 1 or 2 months in vivo showed that they were responsive to glucose stimulation with increase in insulin secretion into the perfusate. The results demonstrated that FK506 significantly prolonged pig islet survival in two rat strains and suggested that it is an effective immunosuppressant for the xenotransplantation model.
FK506是一种新型强效免疫抑制剂，已被证明在延长胰岛同种异体移植存活时间方面有效。本研究旨在确定其在两种不同品系大鼠受体中延长猪胰岛异种移植存活时间的效果。总共测试了两种剂量的FK506，分别为每天1或2mg/kg，持续2周，然后每周一次，作为单一疗法，观察其对近交系ACI大鼠和远交系Wistar大鼠纯化或未纯化成年猪胰岛肾被膜下异种移植存活的影响。组织学评估表明，每天2mg/kg的FK506显著延长了纯化猪胰岛异种移植的存活时间，在三只ACI受体中的两只中存活时间达到了7.5个月。较低剂量FK506单一疗法或未纯化猪胰岛移植导致移植存活时间比对照组延长，但短于每天2mg/kg的FK506。存活的猪胰岛异种移植外观正常，通过胰岛素和胰高血糖素免疫组化染色易于识别，并通过我们实验室开发的抗猪胰岛特异性单克隆抗体克隆P44免疫组化染色进一步证实。单核细胞浸润，主要是CD8阳性T细胞亚群，随着受体中移植物存活时间的延长而增加。到7.5个月时，大多数异种移植的胰岛细胞被细胞浸润所包围。对在体内存活1或2个月的猪胰岛进行的体外灌注研究表明，它们对葡萄糖刺激有反应，灌注液中胰岛素分泌增加。结果表明，FK506显著延长了两种大鼠品系中猪胰岛的存活时间，提示它是异种移植模型的一种有效免疫抑制剂。
