A TOLERANCE APPROACH TO XENOTRANSPLANTATION

异种移植的耐受方法

• 批准号: 7464045
• 负责人: DAVID H SACHS
• 金额: $ 0.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464045
• 关键词: TOLERANCE; APPROACH; XENOTRANSPLANTATION

DESCRIPTION (provided by applicant): Xenotransplantation offers the best near-term hope for satisfying the critical limitation imposed on the field of transplantation today by the severe shortage of cadaveric allogeneic organs. Our studies in the previous Project period of this Program Project grant have made considerable progress, and organ survivals of both heart and kidney xenotransplants from pigs to baboons are now measured in months rather than days. A major factor in this improved survival has been the development of a new, knock-out strain of miniature swine (GalT-KO), which do not express the Gal epitope on their cells, thus avoiding the severe rejection previously caused by natural anti-Gal antibodies. We have also shown that the greatest improvement in organ survivals using these new donors is observed using protocols designed to induce tolerance. Nevertheless, additional improvements will be required before this technology is ready for clinical application. This renewal application brings together five Projects devoted to the most promising approaches and the most pressing problems in this field of research: 1) tolerance induction through vascularized thymic transplantation; 2) tolerance induction through mixed chimerism; 3) modeling of tolerance in mice with human immune systems; 4) Viral pathogenesis in Xenotransplantation; and 5) thromboregulatory barriers to Xenotransplantation. All of these Projects-are highly interactive, and utilize numerous shared resources, many of which will be made available through the large animal core. The work will be carried out in a unique environment, which provides interactions with scientists working in basic and cellular immunology and working on relevant small and large animal models in the same research center, as well as with clinicians committed to taking new therapies to clinical applications. PROJECT 1: Use of GalT-KO Vascularized Thymic Transplantation for the Induction of Xenogeneic Tolerance in Baboons (Yamada, K.) PROJECT 1 DESCRIPTION (provided by applicant): The overall objective of Project 1 is to induce durable tolerance across a pig-to-baboon xenogeneic barrier through transplantation of vascularized thymic grafts. For this purpose, we will: 1) optimize our immunosuppressive drug regimen: We have demonstrated previously that vascularized thymic grafts support thymopoiesis and induce transplant tolerance across fully mismatched allogeneic barriers. In this xenogeneic model, we will attempt to optimize the immunomodulatory treatment regimen required to achieve durable thymus engraftment; 2) determine whether the engrafted thymus can induce tolerance to a kidney xenograft from an inbred donor animal genetically identical to the thymus donor. If successful, the strategy will be extended to simultaneous thymus plus kidney xenotransplantation; and 3) elucidate the mechanism of donor thymus-induced tolerance, using in vitro assays and focusing on the specificity of tolerance across this species barrier. These studies will be highly interactive with other Projects in this PPG. Thus, the optimal treatment regimen will be modified, if necessary, on the basis of results from a mouse model of pig-to-primate tolerance through thymus transplantation being investigated by Sykes and colleagues in Project 3. If eventual antibody-mediated rejection cannot be effectively prevented through thymic transplantation, we will attempt to induce B-cell tolerance by combining thymic transplantation with hematopoietic transplantation, being studied in Project 2. We will also collaborate with Project 5 on the mechanism of any post-transplant coagulation disorders observed. Together, we hope these studies will provide new insights into the potential role of thymic transplantation in the induction of transplantation tolerance.

描述（由申请人提供）：异种移植为满足当今由于尸体同种异体器官严重短缺而对移植领域造成的严重限制提供了最好的近期希望。我们在该计划项目拨款的前一个项目期间的研究取得了相当大的进展，从猪到狒狒的心脏和肾脏异种移植的器官存活率现在以月而不是天来衡量。提高存活率的一个主要因素是开发了一种新的小型猪基因敲除品系（GalT-KO），该品系在其细胞上不表达 Gal 表位，从而避免了先前由天然抗-GalT-KO 引起的严重排斥反应。半乳糖抗体。我们还表明，使用这些新供体的器官存活率的最大改善是通过使用旨在诱导耐受性的方案观察到的。然而，在这项技术准备好投入临床应用之前，还需要进一步的改进。这一更新申请汇集了五个项目，致力于解决该研究领域中最有前途的方法和最紧迫的问题：1）通过血管化胸腺移植诱导耐受； 2) 通过混合嵌合诱导耐受； 3) 具有人类免疫系统的小鼠的耐受性模型； 4）异种移植中的病毒发病机制； 5) 异种移植的血栓调节障碍。所有这些项目都具有高度互动性，并利用大量共享资源，其中许多资源将通过大型动物核心提供。这项工作将在一个独特的环境中进行，该环境可以与在同一研究中心从事基础和细胞免疫学工作并研究相关小型和大型动物模型的科学家以及致力于将新疗法应用于临床的临床医生进行互动。 项目 1：使用 GalT-KO 血管化胸腺移植来诱导狒狒异种耐受性（Yamada, K.） 项目 1 描述（由申请人提供）：项目 1 的总体目标是通过血管化胸腺移植物的移植来诱导跨越猪与狒狒异种屏障的持久耐受性。为此，我们将：1）优化我们的免疫抑制药物治疗方案：我们之前已经证明，血管化胸腺移植物支持胸腺生成并诱导跨越完全不匹配的同种异体屏障的移植耐受。在这个异种模型中，我们将尝试优化实现持久胸腺植入所需的免疫调节治疗方案； 2) 确定移植的胸腺是否可以诱导对来自与胸腺供体基因相同的近交供体动物的肾异种移植物的耐受性。如果成功，该策略将扩展到同步胸腺加肾脏异种移植； 3) 使用体外测定阐明供体胸腺诱导耐受的机制，并重点关注跨越该物种屏障的耐受特异性。这些研究将与本 PPG 中的其他项目高度互动。因此，如有必要，最佳治疗方案将根据 Sykes 及其同事在项目 3 中研究的通过胸腺移植获得猪对灵长类动物耐受性的小鼠模型的结果进行修改。通过胸腺移植有效预防，我们将尝试通过将胸腺移植与造血移植相结合来诱导B细胞耐受，这正在项目2中进行研究。我们还将与项目5合作研究任何移植后凝血障碍的机制观察到。总之，我们希望这些研究将为胸腺移植在诱导移植耐受中的潜在作用提供新的见解。