Alpha1 Anti-trypsin Enhances Islet Autograft Survival

 描述(申请人提供)：胰岛移植的一个主要挑战是避免门脉内胰岛输注后早期胰岛破坏和原发无功能。由于这些问题，一个受者在同种异体胰岛移植后需要至少两个供体才能达到正常血糖(对于1型糖尿病患者，T1D)，只有大约三分之一的患者在自体胰岛移植后达到胰岛素非依赖性(对于慢性胰腺炎患者)。目前，在接受胰岛移植的患者中，没有旨在提高胰岛移植后移植物存活率的介入性方案。因此，迫切需要有效的治疗方法来促进胰岛细胞的植入，提高移植后的存活率。α1抗胰蛋白酶(AAT)是一种丝氨酸蛋白酶抑制剂，可抑制弹性蛋白酶、胰蛋白酶等多种酶的活性。AAT表现出很强的抗炎和抗凋亡特性，并促进血管形成。在移植围术期输注AAT可保护小鼠、猪和非人灵长类动物的胰岛免受免疫排斥反应，并保护胰岛/β细胞功能，这在自体、异体和异种胰岛移植环境中都有体现。在这一框架下，我们计划在南卡罗来纳医科大学进行一项临床研究，以评估人纯化的AAT Prolastin-C(Grifols Inc)在预防慢性胰腺炎患者自体胰岛移植中的死亡和功能障碍方面的疗效。在这项研究中，我们将进一步验证AAT在小鼠肝内胰岛移植模型中的保护作用，该模型使用来自身体供者和CP患者的人胰岛，评估AAT在消除促炎症损伤、胰岛死亡和延迟血管重建方面的作用，这些可能是导致移植后原发胰岛无功能和胰岛破坏的原因之一。此外，我们还将评估在CP患者行全胰腺切除和自体胰岛移植后，在移植围术期应用AAT预防外科糖尿病和改善血糖控制的效果。AAT用于治疗肺气肿已超过25年，具有良好的安全性记录。胰岛自体移植模型提供了一个独特的机会来评估在没有免疫反应、自身免疫复发和胰岛素抵抗的情况下AAT对人类胰岛的直接影响。这些研究的结果不仅是预防CP患者术后糖尿病的迫切需要，而且可以作为一个强大的平台，在此基础上解决T1D患者更复杂的同种异体胰岛细胞移植问题。

 DESCRIPTION (provided by applicant): A major challenge in islet transplantation is avoiding early islet destruction and primary nonfunction after intraportal islet infusion. Because of these issues, at least two donors are needed for one recipient to achieve euglycemia after allogeneic islet transplantation (for patients with type 1 diabetes, T1D), and only around 1/3 of patients become insulin-independent after autologous islet transplantation (for patients with chronic pancreatitis, CP). Currently, no interventional protocols are in place with the goal to increase th survival of islet graft following transplantation in patients receiving islet transplantation. Thus effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Alpha1 anti-trypsin (AAT) is a serine proteinase inhibitor that inhibits various enzymes including elastase, trypsin and others. AAT manifests strong anti-inflammatory and anti-apoptotic properties and promotes vascularization. AAT infusion during peritransplantation period protects islets from immune rejection and preserves islets/β cell function in mice, pigs, and non-human primates, as manifested in autologous, allogeneic and xenogeneic islet transplant settings. Given this framework, we plan to conduct a clinical study to evaluate the therapeutic effects of the human purified AAT, Prolastin-C (Grifols Inc), in the prevention of islet death and dysfunction in autologous islet transplantation for chronic pancreatitis patients at the Medical University of South Carolina. In this study, we will further validate the protective effects of AAT observed in mice intrahepatic islet transplantation models using human islets from cadaveric donors and CP patients, by evaluating the effect of AAT in abrogating proinflammatory injury, islet death, and delayed revascularization that might contribute to primary islet nonfunction and islet destruction post transplantation. Furthermore, we will assess the efficacy of AAT administration during peritransplantation period for the prevention of surgical diabetes and the improvement of glycemic control after total pancreatectomy and islet autotransplantation in CP patients. Having been used for the treatment of pulmonary emphysema for more than 25 years, AAT has excellent safety record. The islet autotransplantation model offers a unique opportunity to assess the direct effect of AAT on human islets in the absence of an immune response, recurrence of autoimmunity, and insulin resistance. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but can serve as a powerful platform on which to address the more complex allogeneic islet cell transplantation for patients with T1D.