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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：胰岛移植的一个主要挑战是避免门静脉内胰岛输注后的早期胰岛破坏和原发性无功能。由于这些问题，一个接受者至少需要两个供体才能在同种异体胰岛移植后实现血糖正常。患有 1 型糖尿病 (T1D) 的患者，只有约 1/3 的患者在自体胰岛移植后变得不依赖胰岛素（对于慢性胰腺炎患者，目前，尚无旨在提高接受胰岛移植的患者移植后胰岛存活率的干预方案，因此迫切需要能够促进胰岛细胞植入并促进移植后存活的有效疗法。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，具有很强的抗炎和抗凋亡作用，并促进血管化。围移植期间的 AAT 输注可以保护小鼠、猪和非人灵长类动物中的胰岛免受免疫排斥，并保留胰岛/β细胞功能，正如自体、同种异体和异种胰岛移植中所表现的那样。鉴于此框架，我们计划进行临床研究。研究评估人纯化 AAT、Prolastin-C（Grifols Inc）在预防慢性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，我们将通过评估 AAT 在消除促炎性损伤方面的作用，进一步验证在使用来自尸体供体和 CP 患者的人类胰岛的小鼠肝内胰岛移植模型中观察到的 AAT 的保护作用。、胰岛死亡和血运重建延迟可能导致移植后原代胰岛功能丧失和胰岛破坏。此外，我们将评估围移植期间 AAT 给药预防的功效。 AAT 用于治疗肺气肿已超过 25 年，具有良好的安全性记录，胰岛自体移植模型为评估 CP 患者的全胰腺切除术和胰岛移植后的血糖控制提供了独特的机会。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迫切需要用于预防术后糖尿病。 CP 患者，但可以作为一个强大的平台来解决 T1D 患者更复杂的同种异体胰岛细胞移植问题。