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

项目1：PI：DKC库珀（摘要） 实验性异种移植（xenoTx），以猪器官移植（Tx）的形式在非人类中进行 灵长类动物，在过去10年中取得了重大进展，因为这个NIAID资助机制是 介绍早期免疫排斥和凝血失调的问题已经大大减少， 但越来越多的证据表明，炎症反应可能激活免疫系统和/或 加剧凝血功能障碍 在项目1中将研究的总体假设是，炎症反应在炎症反应中起作用。 在猪肾和心脏移植失败后Tx到狒狒中显著作用，及其预防或抑制 会导致移植物存活时间延长抗炎药延长移植物存活时间的机制 生存，例如，通过降低先天性或适应性免疫应答，或通过使凝血功能障碍最小化， 将进行全面调查。因此，本提案旨在确认， (i)独特的多基因猪（即，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 免疫应答和凝血失调的影响），（ii）有效的免疫抑制（IS） 方案，和（iii）靶向抗炎方案将一起允许维持生命的一致功能。 猪肾脏和心脏> 6个月，无排斥反应或凝血病。 在目标1（在匹兹堡进行的研究）中，我们将探讨选定的抗炎药对 接受来自多基因猪的肾脏并使用经证实的IS的狒狒的生命支持肾移植存活率 （在本五年供资期内制定的）。如果预期结果不一致， 实现，我们将从猪移植肾脏（2016 - 17年提供给我们），表达不同/额外的 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需的，或者，在心脏的Tx之后， 多基因猪（+/-有效的抗炎方案），IS方案可以最小化，或 省略抗凝，从而降低长期治疗的风险，例如，机会性感染或出血。 将在支持生命的原位模型中评估有前途的方法。 所提出的研究在几个方面是创新的-（i）独特的新型多基因猪，（ii） 随后获得具有可能有利的遗传操作的其他猪，（iii）研究 炎症反应在xenoTx中的作用。拟议研究的成功将使临床试验 作为消除目前对死亡人体器官依赖的第一步， Tx可用于大量患者。

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.