Novel Strategies to Increase Insulin Independence after Islet Autotransplantation

描述（由申请人提供）： 全胰腺切除术联合胰岛自体移植（TP-IAT）目前正在被用于治疗顽固性疼痛和预防慢性胰腺炎患者的“脆性”糖尿病。与TP-IAT相关的主要问题是可用于移植的胰岛的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、促炎细胞因子等）在门静脉内输注后立即发生凋亡时，多达50-60%的胰岛细胞发生凋亡。在胰岛细胞团的收获、分离和植入过程中被诱导。尽管我们的TP-IAT患者的生活质量得到了显著改善，但只有25%的患者成为胰岛素非依赖性患者（术前>85%），19%的患者需要最低限度的胰岛素替代（<10 u/天），其余患者在手术后发展为胰源性糖尿病。产生更“健壮”的胰岛以抵抗诱导细胞凋亡的应激源的策略对于预防手术糖尿病的发作和提高人类胰岛自体移植的效率是非常有吸引力的。在过去的10年里，我们一直致力于探索可以预防同种异体移植治疗1型糖尿病患者后胰岛细胞死亡的策略。我们的数据表明，诱导的保护基因，血红素加氧酶-1（HO-1），或暴露HO-1酶活性的产物，一氧化碳（CO），保护胰岛同种异体移植物从移植后的免疫排斥反应。HO-1基因在慢性胰腺炎患者胰岛中的表达显著低于健康人，HO-1诱导可保护胰岛免受缺氧诱导的细胞死亡。此外，在小鼠胰岛移植模型中，用可生物降解的聚乳酸-共-乙醇酸（PLGA）纳米颗粒包封胰岛也保护胰岛免于凋亡。我们推测，诱导HO-1/CO暴露，结合胰岛包裹，可以使人类胰岛对损伤更具抵抗力，并导致移植后更好的存活率，使更多的慢性胰腺炎患者在TP-IAT后可以摆脱糖尿病。在这项提案中，我们的目标是开发一种新的HO-1/CO为基础的胰岛包封方案，可以使胰岛更抵抗隔离期间和移植后遇到的损伤，使更多的慢性胰腺炎患者可以在TP-IAT后无糖尿病。我们强大的研究团队，包括胰岛移植生物学家，胰岛移植外科医生，内分泌学家和生物工程专家，以及我们在MUSC的最先进的cGMP设施提供了一个方便和强大的平台，可以促进我们的研究结果从实验室到床边的翻译。

DESCRIPTION (provided by applicant): Total pancreatectomy with islet autotransplantation (TP-IAT) is currently being performed to treat intractable pain and to prevent "brittle" diabetes in well-selected patients with chronic pancreatitis. A major problem associated with TP-IAT is that the number of islets available for transplantation is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis immediately after intraportal infusion when transplantation-associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines, etc.) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality of life are significantly improved in our TP-IAT patients, ony 25% of them become insulin independent (compared to >85% pre-operatively), 19% require minimal insulin (<10u/day) replacement and the rest develop pancreatogenic diabetes after surgery. Strategies that produce islets more "robust" to resist stressors that induce ¿ cell apoptosis are extremely appealing to prevent onset of surgical diabetes and to improve the efficiency of human islet auto-transplantation. We have been focused on exploring strategies that can prevent islet ¿ cell death after allogeneic transplantation to treat patient with type 1 diabetes over the past 10 years. Our data indicate that induction of a protective gene, heme oxygenase-1 (HO-1), or exposing the product of HO-1 enzymatic activity, carbon monoxide (CO), protects islet allografts from immune rejection after transplantation. HO-1 gene expression was dramatically reduced in islets from chronic pancreatitis patient compared to those from healthy individual and HO-1 induction protects islets from hypoxia-induced cell death. Moreover, encapsulating islets with biodegradable poly-lactic-co-glycolic acid (PLGA) nanoparticles also protect islets from apoptosis in a murine islet transplantation model. We hypothesize that induction of HO-1/CO exposure, in combination with islet encapsulation, can make human islets more resistant to injuries and lead to better survival after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. In this proposal, we aim to develop a novel HO-1/CO-based islet encapsulation protocol that can make islets more resistant to injuries encountered during isolation and after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. Our strong research team that includes islet transplantation biologists, islet transplantation surgeons, endocrinologists and bioengineering experts, and our state-of-the-art cGMP facility at MUSC offers a convenient and powerful platform that can facilitate the translation of our research findings from bench to bedside.