Alpha1 Anti-trypsin Enhances Islet Autograft Survival

Alpha1 抗胰蛋白酶可增强自体胰岛移植物的存活率

• 批准号: 9182888
• 负责人: Hongjun Wang
• 金额: $ 33.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182888
• 关键词: Acute-Phase Proteins; Address; Adverse effects; Allogenic; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Area Under Curve; Autoimmunity; Autologous; Autologous Transplantation; Beta Cell; Biometry; C-Peptide; Cadaver; Cell Death; Cell Proliferation; Cell physiology; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complex; Cyclic GMP; Data; Diabetes Mellitus; Discipline of Nursing; Dose; Elastases; Engraftment; Ensure; Enzymes; Family suidae; Functional disorder; Goals; Hour; Human; Immune; Immune response; Inflammatory; Infusion procedures; Injury; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Islets of Langerhans Transplantation; Lead; Leukocyte Elastase; Medical; Modeling; Mus; NOD/SCID mouse; Nurses; Operative Surgical Procedures; Patients; Peptide Hydrolases; Play; Postoperative Period; Prevention; Prolastin; Property; Protective Agents; Protocols documentation; Pulmonary Emphysema; Quality of life; Randomized Clinical Trials; Recurrence; Research; Role; Safety; Serine Proteinase Inhibitors; Serum; Services; South Carolina; Testing; Therapeutic Effect; Time; Tissues; Total Pancreatectomy; Translating; Transplantation; Treatment Protocols; Trypsin; Universities; Vascularization; alpha 1-Antitrypsin; bench to bedside; chronic pancreatitis; effective therapy; experience; glycemic control; improved; intrahepatic; islet; mouse model; non-diabetic; nonhuman primate; polypeptide C; prevent; protective effect; public health relevance

 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.

 描述（申请人提供）：胰岛移植的一个主要挑战是避免门静脉内胰岛输注后早期胰岛破坏和原发性无功能。由于这些问题，在同种异体胰岛移植后，一个接受者需要至少两个供体才能实现功能正常（对于1型糖尿病患者，T1 D），并且只有约1/3的患者在自体胰岛移植后成为胰岛素非依赖性（对于慢性胰腺炎患者，CP）。目前，没有干预方案的目的是增加接受胰岛移植的患者移植后胰岛移植物的存活率。因此，有效的治疗，可以促进胰岛细胞移植和促进移植后的生存是迫切需要的。α 1抗胰蛋白酶（AAT）是一种丝氨酸蛋白酶抑制剂，可抑制多种酶，包括弹性蛋白酶、胰蛋白酶等。AAT表现出强烈的抗炎和抗凋亡特性，并促进血管形成。在移植围期期间输注AAT保护胰岛免受免疫排斥，并在小鼠、猪和非人灵长类动物中保留胰岛/β细胞功能，如在自体、同种异体和异种胰岛移植环境中所表现的。在此框架下，我们计划在南卡罗来纳州医科大学进行一项临床研究，以评价人纯化AAT Prolastin-C（Grifols Inc）在预防慢性胰腺炎患者自体胰岛移植中胰岛死亡和功能障碍方面的治疗效果。在这项研究中，我们将进一步验证在小鼠肝内胰岛移植模型中观察到的AAT的保护作用，该模型使用来自尸体供体和CP患者的人胰岛，通过评估AAT在消除促炎性损伤、胰岛死亡和延迟血运重建中的作用，这些损伤可能导致移植后原发性胰岛无功能和胰岛破坏。此外，我们将评估在移植围术期给予AAT预防CP患者全胰腺切除术和胰岛自体移植术后手术糖尿病和改善血糖控制的疗效。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AAT对人类胰岛的直接影响，在没有免疫应答，自身免疫复发，和胰岛素抵抗。这些研究的结果不仅迫切需要预防CP患者术后糖尿病，而且可以作为一个强大的平台，解决T1 D患者更复杂的同种异体胰岛细胞移植问题。