Genetically-engineered pig kidney transplantation in baboons: reducing the adaptive immune response and monitoring graft function

狒狒基因工程猪肾移植：降低适应性免疫反应并监测移植物功能

• 批准号: 10427413
• 负责人: DAVID KC COOPER
• 金额: $ 84.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427413
• 关键词: Attention; Chronic; Dialysis procedure; End stage renal failure; Family suidae; Genetic Engineering; Immune; Immune response; Immunologic Monitoring; Immunologics; Injury; Innate Immune Response; Kidney; Kidney Transplantation; Knowledge; Lead; Life; Measures; Modeling; Organ; Organ Transplantation; Papio; Pathway interactions; Patients; Physiological; Primates; Regimen; Renal function; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic immunosuppression; Time; Transgenic Organisms; Xenograft procedure; adaptive immune response; base; genetic manipulation; graft function; improved; nonhuman primate; novel; programmed cell death ligand 1

GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES PROJECT 1: Genetically-engineered pig kidney transplantation in baboons: reducing the adaptive immune response and monitoring graft function (Project Lead: David K.C Cooper) PROJECT SUMMARY/ABSTRACT Considerable advances have been made in the results of life-supporting genetically- engineered (GE) pig kidney transplantation (Tx) in nonhuman primates (NHPs), with graft and recipient survival in months or even years. Since the barrier of the innate immune response has largely been overcome, we will direct most of our attention to (i) reducing the adaptive immune response, and (ii) investigating the potential physiological incompatibilities between pigs and NHPs. We will first test kidney transplants from pigs with the most advanced genetic- engineering to date, i.e., pigs with 8 genetic manipulations (8GE pigs), all aimed towards protecting the kidney from the primate immune response. We will compare two immunosuppressive regimens, in one using a novel costimulation blockade agent that has not been tested in a xenotransplantation model previously. Using the preferred regimen, we will then transplant kidneys from 8GE pigs additionally transgenic for expression of programmed death ligand 1 (PG-L1), which should allow successful organ Tx with a reduced exogenous immunosuppressive therapy. We predict that kidneys from these pigs, using the preferred immunosuppressive regimen, will function for 6 months in the absence of immune-related injury, thus allowing a comprehensive study of renal function to determine whether there are physiological incompatibilities that might require attention. Offering patients with end-stage renal disease a timely pig kidney transplant without excessive exogenous immunosuppressive therapy would allow many more patients to receive kidney transplants, and reduce the need for chronic dialysis. 1

基因工程猪器官移植到狒狒体内： 免疫学和功能研究 项目1：狒狒的基因工程猪肾移植：减少 适应性免疫反应和监测移植物功能（项目负责人：大卫K. C （库珀） 项目总结/摘要 在维持生命的基因方面取得了相当大的进展， 在非人灵长类动物（NHP）中进行工程化（GE）猪肾移植（Tx）， 接受者存活数月甚至数年。由于先天免疫反应的屏障 在很大程度上已经克服，我们将把我们的注意力主要集中在（i）减少适应性免疫 反应，和（ii）调查猪和 NHP。 我们将首先测试猪的肾脏移植，这些猪具有最先进的遗传- 迄今为止，即，8个基因操作的猪（8 GE猪），所有目的都是为了 保护肾脏免受灵长类动物免疫反应的影响。我们将比较两个 免疫抑制方案，其中一种使用新的共刺激阻断剂， 之前在异种移植模型中进行了测试。使用首选方案，我们将 然后移植来自另外转基因的8 GE猪的肾脏，以表达程序化的 死亡配体1（PG-L1），这应该允许成功的器官Tx与减少外源性 免疫抑制治疗。我们预测，这些猪的肾脏，使用首选的 免疫抑制方案，将在没有免疫相关损伤的情况下起作用6个月， 从而允许对肾功能进行全面研究以确定是否存在 可能需要注意的生理上的不相容。 为终末期肾病患者提供及时的猪肾移植， 过度的外源性免疫抑制治疗会使更多的患者接受 肾移植，并减少对慢性透析的需求。 1