Krishnan Rahul, Buder Brian, Alexander Michael, Foster Clarence E, Lakey Jonathan Rt
1 Department of Surgery, University of California Irvine, Orange, CA. 2 Department of Biomedical Engineering, University of California, Irvine, Irvine, CA.
Transplantation. 2015 Apr;99(4):710-6. doi: 10.1097/TP.0000000000000667.
Porcine islet xenotransplantation has been demonstrated in many animal studies to cure experimentally induced diabetes. However, several issues currently impede the translation of porcine islet xenotransplantation to sustained insulin independence clinically. Although adult pigs have mature islets that secrete insulin in response to a glucose challenge, and are physiologically similar to humans, there are logistical considerations with adult porcine tissue that are not present with juvenile porcine tissue. To circumvent these issues, we have identified 18- to 21-day-old preweaned juvenile pigs as islet donors as we have previously demonstrated superior islet yields and function from juvenile pigs using our islet isolation protocols.
We evaluated the efficacy of islets isolated from 18- to 24-day-old Yorkshire swine in vitro using a standard glucose-stimulated insulin response assay, and in vivo after xenotransplantation under the kidney capsule of streptozotocin-induced 8- to 10-week-old male athymic nude mice. The mice were monitored for a period of 60 days after transplantation, after which the grafts were explanted and analyzed.
Diabetic athymic nude mice transplanted with 1500 to 3000 islet equivalents (IEq) of islets achieved sustained normoglycemia for up to 60 days after islet transplantation. When the grafts were explanted with the kidney, a rapid return to hyperglycemia was observed.
Efficacy and dose-titration studies evaluating these islets in immunocompetent and nonobese diabetic mouse models are underway. The results of these studies will permit application for nonhuman primate and pivotal clinical trials in human diabetic patients in the near future.
在许多动物研究中已证实猪胰岛异种移植可治愈实验性诱导的糖尿病。然而，目前有几个问题阻碍了猪胰岛异种移植在临床上实现持续的胰岛素非依赖状态。尽管成年猪具有成熟的胰岛，能在葡萄糖刺激下分泌胰岛素，且在生理上与人类相似，但成年猪组织存在一些后勤方面的考虑因素，而幼年猪组织则不存在这些问题。为规避这些问题，我们已确定18至21日龄未断奶的幼年猪作为胰岛供体，因为我们之前使用我们的胰岛分离方案已证明幼年猪的胰岛产量和功能更优。
我们使用标准的葡萄糖刺激胰岛素反应试验在体外评估了从18至24日龄约克夏猪分离的胰岛的功效，并在体内将其异种移植到链脲佐菌素诱导的8至10周龄雄性无胸腺裸鼠的肾包膜下后进行了评估。移植后对小鼠进行了60天的监测，之后取出移植物并进行分析。
移植1500至3000个胰岛当量（IEq）胰岛的糖尿病无胸腺裸鼠在胰岛移植后长达60天实现了持续的血糖正常。当将移植物与肾脏一起取出时，观察到血糖迅速恢复到高血糖状态。
正在免疫活性和非肥胖糖尿病小鼠模型中进行评估这些胰岛的功效和剂量滴定研究。这些研究的结果将允许在不久的将来应用于非人灵长类动物和人类糖尿病患者的关键临床试验。
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