Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
Department of Medicine, Seoul National University College of Medicine, Seoul, Korea.
Xenotransplantation. 2018 Jan;25(1). doi: 10.1111/xen.12362. Epub 2017 Nov 12.
Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation. We report the long-term survival of adult wild-type pig islets and successful retransplantation in nonhuman primates using a protocol comprising induction with MD-3 mAb and maintenance with anti-CD154 mAb and sirolimus.
Eleven rhesus monkeys were assigned to three groups. Group 1 (n = 4) involved treatment with MD-3 induction, short-term (<4 months) administration of anti-CD154 mAb, and maintenance therapy with sirolimus. Group 2 (n = 4) involved treatment with MD-3 induction and long-term maintenance therapy with anti-CD154 mAb and sirolimus. Group 3 (n = 3) involved only maintenance therapy with anti-CD154 mAb and sirolimus. Diabetes was induced in monkeys by streptozotocin, and pig islets (61 000-112 000 IEQ/kg for each transplant; up to 280 000 IEQ/kg per recipient) were infused through the portal vein. The in vivo functional potency of the isolated islets was tested by minimal model transplant in streptozotocin-induced diabetic NOD/SCID mice, and the mean AUC of blood glucose level divided by the number of follow-up days was calculated.
The islet grafts survived more than 6 months (between 225 and 727 days) in nine of 12 transplants of MD-3-treated groups 1 and 2, whereas in the absence of MD-3 mAb, survival was <40 days. In three transplants of the MD-3-treated Group 2, functional graft survival was only for 104, 125, and 154 days. In these cases, a retrospective analysis suggested that the relatively short survival duration was associated with the relatively high AUC value in the NOD/SCID bioassay. Notably, when retransplantation was performed in Group 3, blood glucose control was extended up to 956 days, which was supported by MD-3 mAb-based suppression of adaptive immunity. No replication of cytomegalovirus genes was observed.
Long-term survival of pig islet xenografts and successful retransplantation were achieved with MD-3 mAb-based immunosuppression regimen in this pig-to-monkey transplantation model. It should be emphasized that these encouraging results were achieved following the transplantation of islets from pigs that had not been genetically modified. Considering that it is possible to further substantially reduce the destruction of grafted islet using genetically modified pig islet, the islet requirement could be reduced and much longer graft survival can be achieved.
猪胰岛异种移植是同种异体移植的一种很有前途的替代方法。然而，猪和灵长类动物之间广泛的免疫屏障限制了移植物的长期存活。MD-3 是一种新型单克隆抗体（mAb），可识别人 ICAM-1 的特定表位，通过阻止树突状细胞成熟使 T 细胞耐受异种移植物。我们报告了使用包括 MD-3 mAb 诱导和抗 CD154 mAb 和西罗莫司维持的方案，成年野生型猪胰岛的长期存活和在非人类灵长类动物中的成功再移植。
11 只恒河猴被分为三组。第 1 组（n=4）接受 MD-3 诱导治疗、短期（<4 个月）抗 CD154 mAb 治疗和西罗莫司维持治疗。第 2 组（n=4）接受 MD-3 诱导和长期抗 CD154 mAb 和西罗莫司维持治疗。第 3 组（n=3）仅接受抗 CD154 mAb 和西罗莫司维持治疗。猴子通过链脲佐菌素诱导糖尿病，门静脉输注 61000-112000IEQ/kg（每个移植体；每个受者高达 280000IEQ/kg）的猪胰岛。通过在链脲佐菌素诱导的 NOD/SCID 小鼠中的最小模型移植测试分离胰岛的体内功能效力，并计算血糖水平的平均 AUC 除以随访天数。
在 12 次 MD-3 治疗组 1 和 2 的移植中，9 次胰岛移植物存活超过 6 个月（225 至 727 天），而在没有 MD-3 mAb 的情况下，存活时间<40 天。在 MD-3 治疗组 2 的 3 次移植中，功能移植物的存活时间仅为 104、125 和 154 天。在这些情况下，回顾性分析表明，相对较短的存活时间与 NOD/SCID 生物测定中的相对较高的 AUC 值有关。值得注意的是，当在第 3 组中进行再移植时，血糖控制延长至 956 天，这得益于基于 MD-3 mAb 的适应性免疫抑制。未观察到巨细胞病毒基因的复制。
在这种猪到猴移植模型中，使用基于 MD-3 mAb 的免疫抑制方案实现了猪胰岛异种移植物的长期存活和成功再移植。应该强调的是，这些令人鼓舞的结果是在未经过基因修饰的猪胰岛移植后获得的。考虑到使用基因修饰的猪胰岛可以进一步大大减少移植胰岛的破坏，因此可以减少胰岛的需求，并实现更长的移植物存活时间。
