A Novel Approach to Prevent Surgical Diabetes in Chronic Pancreatitis Patients

描述(申请人提供)：全胰腺切除和自体胰岛移植(IAT)在治疗慢性胰腺炎相关的顽固性疼痛方面是安全和有效的。与IAT相关的一个主要问题是，可供移植的胰岛数量受到严重病变和纤维化的胰腺的影响。此外，多达50-60%的胰岛细胞在门脉内移植后2-3天发生凋亡，在胰岛细胞团的采集、分离和植入过程中，由于移植相关应激因素(缺氧、营养剥夺、活性氧、促炎细胞因子)的诱导，胰岛细胞发生了凋亡。尽管我们的IAT患者的生活质量参数得到了显著改善，但只有25%的患者实现了胰岛素非依赖性(与之相比，胰腺切除术前80%的患者血糖正常)。产生更多“健壮”的胰岛以抵抗诱导细胞凋亡的应激源的策略是提高人类IAT效率的一种有吸引力的和有前途的方法。在过去的10年里，我们一直致力于在同种异体移植的背景下，探索能够改善胰岛细胞存活和功能的策略来治疗1型糖尿病患者。我们的新发现表明，将胰岛暴露于低剂量的一氧化碳(CO，气体或溶解在溶液中)给胰岛供体，或分离的胰岛，可以保护这些胰岛免受应激诱导的细胞凋亡和移植后的免疫排斥反应。进一步研究表明，CO暴露于胰岛供体可上调胰岛中转录因子PPARγ的表达。供者使用PPARγ激动剂治疗大失配胰岛移植可使移植胰岛长期存活(100天) 无需任何额外处理的模型。自体胰岛移植物与同种异体胰岛移植物的损伤相似。 并避免了移植后免疫排斥反应的额外复杂性。因此，诸如PPARγ激活和CO暴露等可以保护人类胰岛免受应激的策略将为接受IAT的慢性胰腺炎患者带来直接好处，并可能成为解决更复杂的同种异体胰岛细胞移植的平台。在这项研究中，我们将检验这样一种假设，即在富含CO的环境中采集胰岛和/或PPARγ诱导的孤立胰岛可以最大限度地减少应激诱导的胰岛凋亡，从而提高存活和功能。我们最先进的cGMP设施定期进行IAT，我们强大的临床和研究团队、临床试验支持、临床试验护理、临床设施、现有患者池和MUSC的生物统计支持提供了强大的平台，可以轻松地将研究成果从工作台转换到床边。一旦研究完成，有望推动胰岛移植领域的发展。

DESCRIPTION (provided by applicant): Total pancreatectomy and islet autotransplantation (IAT) is safe and effective in the management of intractable pain associated with chronic pancreatitis. A major problem associated with IAT is that the number of islets available for transplant is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis at 2-3 days after intraportal transplantation when transplantation associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality-of-life parameters are significantly improved in our IAT patients, only 25% of patients become insulin independent (compared to 80% patients with normoglycemia before pancreatectomy). Strategies that produce more "robust" islets to resist stressors that induce ß cell apoptosis are an appealing and promising method to improve the efficiency of human IAT. Over the past 10 years we have focused on exploring strategies that can improve islet/ß cell survival and function to treat patient with type-1 diabetes in the settingof allogeneic transplantation. Our novel findings indicate that exposing islets to low doses of carbon monoxide (CO, gaseous or dissolved in solutions) to the islet donor, or isolated islets, can protect those islets from stress-induced apoptosis and immune rejection after transplantation. Further study indicates that CO exposure to islet donor up-regulates expression of PPARγ, a transcriptional factor, in isolated islets. Donor treatment with PPARγ agonists leads to long-term (>100 days) survival of transplanted islets in a major mismatch islet transplantation model without any additional treatments. Islet autografts suffer from similar injuries as allograft and are spared the additional complexities of immune rejection response after transplantation. Thus, strategies such as PPARγ activation and CO exposure that can protect human islets from stress will bring immediate benefit to patients with chronic pancreatitis receiving an IAT and potentially serve as a platform on which to address the more complex allogeneic islet cell transplantation. In this study, we will test the hypothesis that stress-induced apoptosis of post IAT islets can be minimized leading to increased survival and function by harvesting islets in a CO-rich environment and/or PPARγ induction is isolated islets. Our state-of-the-art cGMP facility that undertakes IAT on a regular basis, our strong clinical and research team, clinical tral support, clinical trial nursing, clinical facilities, current patient pool and the biostatistics suport at MUSC offers powerful platform that can readily translate research finding from bench to bedside. Once the study is completed, it promises to advance the field of islet transplantation forward.