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

基因工程猪器官移植在狒狒身上的应用： 免疫学和功能研究 项目1：通过基因工程将猪肾移植到狒狒体内：减少 适应性免疫反应和监测移植物功能(项目负责人：David K.C. 库珀) 项目摘要/摘要 在基因维持生命的结果方面已经取得了相当大的进展- 工程化(GE)猪肾移植(TX)在非人灵长类动物(NHP)中，移植和 接受者存活数月甚至数年。因为先天免疫反应的屏障已经 在很大程度上被克服了，我们将把大部分注意力集中在(I)减少获得性免疫上 反应，以及(Ii)调查猪和猪之间潜在的生理不亲和性 国家卫生保健计划。 我们将首先测试拥有最先进基因的猪的肾脏移植- 到目前为止，工程技术，即具有8个基因操作的猪(8GE猪)，所有目标都是 保护肾脏免受灵长类免疫反应的影响。我们将比较两个 免疫抑制方案，其中一种使用了一种新的共刺激阻滞剂，该阻滞剂尚未 之前已经在异种移植模型中进行了测试。使用首选的方案，我们将 然后移植8GE猪的肾脏，并额外转基因表达程序化 死亡配体1(PG-L1)，这应该允许成功的器官TX与减少外源性 免疫抑制疗法。我们预测这些猪的肾脏，使用首选的 免疫抑制方案，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 生理上的不相容可能需要注意。 为终末期肾病患者提供及时的猪肾移植 过量的外源性免疫抑制治疗将允许更多的患者接受 肾移植，并减少慢性透析的需要。 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