Prolonging life-supported pig kidney and heart graft survival in baboons by suppressing inflammation

通过抑制炎症来延长狒狒的猪肾和心脏移植物的存活率

• 批准号: 9115988
• 负责人: DAVID KC COOPER
• 金额: $ 76.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115988
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Attenuated; Blood Coagulation Disorders; Clinical Trials; Coagulation Process; Data; Failure; Family suidae; Functional disorder; Funding; Funding Mechanisms; Genes; Genetic; Genetic Engineering; Graft Survival; Heart; Heart Transplantation; Hemorrhage; Heparin; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Investigation; Kidney; Kidney Transplantation; Life; Modeling; Modification; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Papio; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevention; Primates; Proteinuria; Regimen; Residual state; Risk; Role; TFPI; Therapeutic immunosuppression; Tissues; Transgenes; Xenograft procedure; abstracting; adaptive immunity; base; cytokine; genetic manipulation; graft failure; heart xenograft; human tissue; improved; inflammatory marker; innovation; kidney xenograft; member; nonhuman primate; novel; programs; success; von Willebrand Factor

Project 1: PI: D.K.C. Cooper (Abstract) Experimental xenotransplantation (xenoTx), in the form of pig organ transplantation (Tx) in nonhuman primates, has made major advances during the past 10 years since this NIAID funding mechanism was introduced. The problems of early immune rejection and coagulation dysregulation have been greatly reduced, but there is increasing evidence that an inflammatory response may be activating the immune system and/or amplifying coagulation dysfunction. The overall hypothesis that will be investigated in Project 1 is that an inflammatory response plays a significant role in pig kidney and heart graft failure after Tx into baboons, and that its prevention or suppression will result in prolonged graft survival. The mechanisms whereby anti-inflammatory agents prolong graft survival, e.g., by reducing the innate or adaptive immune response, or by minimizing coagulation dysfunction, will be comprehensively investigated. The current proposal will therefore aim to confirm that the combination of (i) unique multi-gene pigs (i.e., pigs with 6 or 7 genetic modifications to protect their tissues from the primate immune response and from the effects of coagulation dysregulation), (ii) an effective immunosuppressive (IS) regimen, and (iii) a targeted anti-inflammatory regimen will, together, allow consistent function of life-supporting pig kidneys and hearts for >6 months in the absence of rejection or coagulopathy. In Aim 1 (investigated in Pittsburgh), we will explore the effect of selected anti-inflammatory agents on life-supporting kidney graft survival in baboons receiving kidneys from multi-gene pigs and using the proven IS regimen (developed during the present 5-year funding period). If the expected outcome is not consistently achieved, we will transplant kidneys from pigs (available to us in 2016-17) expressing different / additional transgenes that might prove advantageous. In Aim 2 (NHLBI), in the heterotopic (non-life-supporting) heart Tx model we shall investigate whether all components of the previously successful IS regimen are essential or whether, after the Tx of a heart from a multi-gene pig (+/- an effective anti-inflammatory regimen), the IS regimen can be minimized, or anticoagulation omitted, thus reducing the risks of long-term therapy, e.g., opportunistic infection or bleeding. Promising approaches will be evaluated in a life-supporting orthotopic model. The proposed studies are innovative in several respects – (i) unique novel multi-gene pigs, (ii) the subsequent availability of further pigs with possibly advantageous genetic manipulations, (iii) investigation of the role of the inflammatory response in xenoTx. Success in the proposed studies would enable clinical trials of kidney and heart xenoTx as a first step to eliminate current reliance on deceased human organs, making organ Tx available to a greatly expanded number of patients.

项目1：PI：D.K.C.库珀（摘要） 实验性异种移植（xenoTx），以猪器官移植（Tx）的形式在非人类身上进行 自 NIAID 资助机制建立以来，灵长类动物在过去 10 年中取得了重大进展 介绍了。早期免疫排斥和凝血失调的问题大大减少， 但越来越多的证据表明炎症反应可能会激活免疫系统和/或 加剧凝血功能障碍。 项目 1 将研究的总体假设是炎症反应在 Tx 进入狒狒后，在猪肾和心脏移植失败中发挥重要作用，并表明其预防或抑制 将导致移植物存活时间延长。抗炎剂延长移植物的机制 生存，例如通过减少先天性或适应性免疫反应，或通过最大限度地减少凝血功能障碍， 将进行全面调查。因此，当前提案旨在确认以下方面的结合： (i) 独特的多基因猪（即具有 6 或 7 个基因修饰的猪，以保护其组织免受灵长类动物的侵害） 免疫反应和凝血失调的影响），（ii）有效的免疫抑制（IS） 方案，以及（iii）有针对性的抗炎方案将共同实现生命支持功能的一致 在没有排斥或凝血病的情况下，猪肾脏和心脏超过 6 个月。 在目标 1（在匹兹堡进行的研​​究）中，我们将探讨所选抗炎药物对 狒狒接受多基因猪的肾脏并使用经过验证的 IS 来维持生命支持的肾移植存活 治疗方案（在当前 5 年资助期内制定）。如果预期结果不一致 实现后，我们将移植表达不同/附加的猪肾（我们于 2016-17 年提供） 可能被证明是有利的转基因。 在目标 2 (NHLBI) 中，在异位（非生命支持）心脏 Tx 模型中，我们将研究是否 先前成功的 IS 方案的所有组成部分都是必不可少的，或者是否在对心脏进行 Tx 治疗后 多基因猪（+/- 有效的抗炎方案），可以最小化 IS 方案，或 省略抗凝治疗，从而降低长期治疗的风险，例如机会性感染或出血。 有前景的方法将在生命支持原位模型中进行评估。 拟议的研究在几个方面具有创新性——（i）独特的新型多基因猪，（ii） 随后可获得具有可能有利的基因操作的更多猪，（iii）调查 xenoTx 中炎症反应的作用。拟议研究的成功将使临床试验成为可能 肾脏和心脏 xenoTx 是消除目前对已故人体器官依赖的第一步，使器官 Tx 可供更多数量的患者使用。