Pig to Non-Human Primate Islet Xenografts

猪到非人类灵长类动物胰岛异种移植

• 批准号: 7277708
• 负责人: Judith M. Thomas
• 金额: $ 126.55万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-12 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7277708
• 关键词: Adult; Adverse effects; Alabama; Allogenic; Anatomic Sites; Antibodies; Antigens; Cells; Cellular biology; Chronic; Clinical; Collaborations; Condition; Core Facility; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Engineering; Family suidae; Farming environment; Fostering; Galactose; Gene Transfer; Goals; Human; Immune; Immune Tolerance; Immune response; Immunobiology; Immunologic Tests; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotoxins; Infiltration; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kindling (Neurology); Liver; Minnesota; Modeling; Molecular; Monoclonal Antibody HuM291; Muromonab-CD3; Outcome; Pancreas; Patients; Personal Satisfaction; Pharmaceutical Preparations; Proteins; Protocols documentation; Public Health; Purpose; Reporting; Research; Research Personnel; Research Project Grants; Risk; Safety; Scientist; Seasons; Site; Solutions; Source; Supplementation; Survivors; Sus scrofa; T-Lymphocyte; Technology; Therapeutic; Therapeutic immunosuppression; Translations; Transplantation; Transplantation Tolerance; Universities; Xenograft procedure; base; design; diabetes mellitus therapy; diabetic; experience; functional loss; innovation; interest; intrahepatic; islet; islet allograft; islet xenograft; macrophage; multidisciplinary; nonhuman primate; novel; novel strategies; optimism; pre-clinical; prevent; programs; research study; success

DESCRIPTION: Recent clinical reports of allogeneic human islet transplantation provide proof of principle that cell-based diabetes therapy can reverse the course of diabetes mellitus. As demand for islet transplantation increases the human islet donor shortage precludes widespread application. Xenogeneic porcine islets could provide a limitless source of donor cells, if safe and effective protocols are crafted to promote long term islet xenograft survival. The rational design and development of such protocols requires greater understanding of the immunobiology of anti-pig islet immune responses in a preclinical nonhuman primate (NHP) model close to humans. The proposed research program brings together a group of collaborating investigators, combining diverse scientific interests and backgrounds in an endeavor to develop innovative therapeutic approaches for promoting long term pig-to-NHP islet xenograft (XPITx) acceptance without lifelong immunosuppressive therapy. Furthermore, the projects and supporting core facilities are unified in a multidisciplinary effort to elucidate underlying mechanisms related to long term XPITx acceptance and acquired tolerance in diabetic NHP. The program will be centered at the University of Alabama at Birmingham with 2 research projects and 1 administrative core, while the University of Minnesota is the consortium partner with 1 research project and 2 scientific cores. Project 1 will examine the efficacy of tolerance induction to XPITx in diabetic NHP without chronic therapy. The approach will apply a brief (2 wk) tolerance induction protocol that has induced long term allogeneic islet tolerance in NHP. Local and systemic immune adaptations and XPITx outcome will be examined in two anatomic sites, the liver and omental pouch (OP), wherein supplemental immunomodulatory molecules will be delivered. Project 2 will endeavor to engineer the NHP OP to enhance revascularization of the pig islets and to optimize local delivery of immunoregulatory proteins into the islet milieu, including gene transfer using transposon technology in collaboration with Core C. Project 3 will develop low-risk immunotherapeutic strategies to prevent XPITx rejection in liver and OP sites in diabetic NHP, by examining a novel protocol with triple costimulatory blockade. Project 3 will also compare the efficacy and safety of systemic vs. local immunosuppression in the OP XPITx site. Close interactions and data sharing among the projects will accelerate advances in basic understanding and success of NHP XPITx. PROJECT 1: A New Approach to Tolerance in Islet Xenografts (Thomas, J.) DESCRIPTION (provided by applicant) Diabetes mellitus (DM) is a leading public health concern, with over 1 million Type 1 DM patients in the USA. The Edmonton Study showed that intrahepatic pancreas islet transplantation can reverse DM, restoring euglycemia. At present, gradual loss of functional islet mass and a requirement for multiple transplants limit widespread application. With the critical shortage of human donors, there is a need for xenogeneic islets. Porcine islets are appealing, since pig insulin is well tolerated in humans, and pigs are adapted to large scale domestic farming. Unlike normal pig endothelial cells that express the galactose a(1,3) galactose (aGal), to which humans and old world nonhuman primates (NHP) have natural antibodies, adult pig islets express exceptionally low levels of aGal and are not subject to hyperacute rejection. Recent findings from Dr. Hering, showing long term survival of pig-to-NHP islet transplant (XPITx) under chronic immunosuppressive therapy, kindle optimism for clinical translation. The importance of tolerance induction to eliminate lifelong immunosuppressive therapy cannot be over-emphasized, since side effects of this therapy can generate problems as deleterious as the original disease. The goal of the proposed experiments is to develop new approaches that facilitate safe and effective immunosuppression to induce tolerance of pig-to-NHP XPITx, without need for chronic immunosuppressive therapy. The studies will build on our previous experience gained in NHP tolerance, using a strategy of brief anti-CD3 immunotoxin and 15-deoxyspegualin treatment that has yielded NHP islet allograft survivors, drug-free and euglycemic for >5 years post-transplant. This will involve intense immunological testing of the mechanisms involved in the; outcome of pig-to-NHP XPITx: The tolerance induction protocol will be modified to counter the rigorous immune response to discordant XPITx, and examined in both intrahepatic (IH) and omental pouch (OP) sites. Since there is no precedent for NHP xenotolerance, the data will guide the design and implementation of strategic refinements to achieve XPITx acceptance. Accordingly, the aims of the proposed experiments are to: (1) Compare the outcome of pig-to-NHP XPITx in IH vs. OP sites using brief systemic immunosuppression that targets T cells and DC, shown to promote stable tolerance to islet allografts in diabetic NHP; (2) Examine a hypothesis that long term acceptance of XPITx in the OP can be achieved following supplementation of the above tolerance protocol with local immunosuppression. We will examine supplemental local vs. systemic immunosuppression with IL- 10 and anti-LFA-1 to minimize macrophage infiltration; (3) Define the immune mechanisms governing XPITx acceptance or rejection in NHP recipients treated under the immunosuppressive conditions described in the previous aims. These studies are unique and will generate new data on pig-to-NHP XPITx immunobiology and the immune mechanisms influencing development of pig XPITx tolerance.

描述：最近同种异体人类胰岛移植的临床报告提供了基于细胞的糖尿病治疗可以逆转糖尿病病程的原理证明。随着胰岛移植需求的增加，人类胰岛供体短缺阻碍了广泛应用。如果制定安全有效的方案来促进胰岛异种移植物的长期存活，异种猪胰岛可以提供无限的供体细胞来源。此类方案的合理设计和开发需要更好地了解接近人类的临床前非人灵长类动物（NHP）模型中抗猪胰岛免疫反应的免疫生物学。拟议的研究计划汇集了一组合作研究人员，结合不同的科学兴趣和背景，努力开发创新的治疗方法，以促进长期猪到 NHP 胰岛异种移植物 (XPITx) 的接受，而无需终身免疫抑制治疗。此外，这些项目和支持核心设施在多学科努力中得到统一，以阐明与糖尿病 NHP 的长期 XPITx 接受和获得性耐受相关的潜在机制。该项目将以阿拉巴马大学伯明翰分校为中心，拥有 2 个研究项目和 1 个行政核心，而明尼苏达大学是联盟合作伙伴，拥有 1 个研究项目和 2 个科学核心。项目 1 将检查在没有长期治疗的情况下，糖尿病 NHP 中 XPITx 耐受诱导的功效。该方法将应用一个简短的（2 周）耐受诱导方案，该方案已在 NHP 中诱导长期同种异体胰岛耐受。将在两个解剖部位（肝脏和网膜袋（OP））检查局部和全身免疫适应以及 XPITx 结果，其中将递送补充免疫调节分子。项目 2 将致力于改造 NHP OP，以增强猪胰岛的血运重建，并优化免疫调节蛋白局部递送到胰岛环境中，包括与 Core C 合作使用转座子技术进行基因转移。项目 3 将开发低风险免疫治疗策略通过研究具有三重共刺激阻断的新方案来防止糖尿病 NHP 患者肝脏和 OP 部位的 XPITx 排斥。项目 3 还将比较 OP XPITx 站点中全身免疫抑制与局部免疫抑制的功效和安全性。项目之间的密切互动和数据共享将加速 NHP XPITx 的基本理解和成功。 项目 1：胰岛异种移植物耐受的新方法 (Thomas, J.) 描述（由申请人提供） 糖尿病 (DM) 是一个主要的公共卫生问题，美国有超过 100 万 1 型糖尿病患者。埃德蒙顿研究表明，肝内胰岛移植可以逆转糖尿病，恢复正常血糖。目前，功能性胰岛质量的逐渐丧失和多次移植的要求限制了广泛应用。由于人类供体严重短缺，因此需要异种胰岛。猪胰岛很有吸引力，因为猪胰岛素在人类中具有良好的耐受性，而且猪适合大规模的家庭养殖。与表达半乳糖 a(1,3) 半乳糖 (aGal) 的正常猪内皮细胞不同，人类和旧世界非人灵长类动物 (NHP) 对此具有天然抗体，成年猪胰岛表达的 aGal 水平异常低，并且不会受到超急性拒绝。 Hering 博士的最新研究结果显示，猪转 NHP 胰岛移植 (XPITx) 在长期免疫抑制治疗下可长期存活，这为临床转化带来了乐观情绪。诱导耐受对于消除终生免疫抑制治疗的重要性怎么强调都不为过，因为这种疗法的副作用可能会产生与原始疾病一样有害的问题。拟议实验的目标是开发新方法，促进安全有效的免疫抑制，以诱导猪对 NHP XPITx 的耐受，而不需要长期免疫抑制治疗。这些研究将建立在我们之前在 NHP 耐受性方面获得的经验的基础上，使用短暂的抗 CD3 免疫毒素和 15-脱氧镜下尿素治疗策略，该策略已产生 NHP 胰岛同种异体移植物幸存者，移植后 5 年以上，无需药物且血糖正常。这将涉及对所涉及的机制进行深入的免疫学测试；猪对 NHP XPITx 的结果：耐受诱导方案将被修改，以对抗对不一致 XPITx 的严格免疫反应，并在肝内 (IH) 和网膜袋 (OP) 部位进行检查。由于 NHP 异耐受尚无先例，因此该数据将指导战略改进的设计和实施，以实现 XPITx 的接受。因此，拟议实验的目的是：（1）使用针对 T 细胞和 DC 的短暂全身免疫抑制，比较猪对 NHP XPITx 在 IH 与 OP 位点的结果，显示可促进对胰岛同种异体移植物的稳定耐受。糖尿病非人灵长类动物； (2) 检查一个假设，即在补充上述耐受方案和局部免疫抑制后，可以在 OP 中实现 XPITx 的长期接受。我们将检查用 IL-10 和抗 LFA-1 补充局部免疫抑制与全身免疫抑制，以尽量减少巨噬细胞浸润； (3) 定义在前述目标中描述的免疫抑制条件下治疗的 NHP 接受者中控制 XPITx 接受或拒绝的免疫机制。这些研究是独一无二的，将产生关于猪对 NHP XPITx 免疫生物学和影响猪 XPITx 耐受性发展的免疫机制的新数据。