A Novel Approach to Prevent Surgical Diabetes in Chronic Pancreatitis Patients

描述（由申请人提供）：全胰腺切除术和胰岛自体移植（IAT）是治疗慢性胰腺炎相关难治性疼痛安全有效的方法。与IAT相关的一个主要问题是，可用于移植的胰岛数量受到严重病变和纤维化胰腺的损害。此外，当移植相关的应激源（缺氧、营养剥夺、活性氧、促炎症细胞因子）在胰岛细胞团的收获、分离和植入过程中被诱导时，多达50-60%的胰岛细胞在门静脉内移植后2-3天发生凋亡。尽管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独立（相比之下，胰切除术前血糖正常的患者为80%）。产生更“健壮”的胰岛来抵抗诱导ß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和有前途的方法。在过去的10年里，我们一直专注于探索可以改善胰岛/ß细胞存活和功能的策略，以治疗异体移植的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，气态或溶解在溶液中）给胰岛供体或分离的胰岛，可以保护这些胰岛在移植后免受应激诱导的细胞凋亡和免疫排斥。进一步的研究表明，CO暴露于胰岛供体可上调胰岛中转录因子PPARγ的表达。在一个主要的错配胰岛移植中，供体用PPARγ激动剂治疗可导致移植胰岛长期（100天）存活

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.