A Tolerance Approach to Xenotransplantation

描述(申请人提供)：异种移植仍然是近期缓解同种器官严重短缺的最好希望。异种器官移植存活的一个重大进展是开发了一种小型猪的敲除品系(Galt-KO)，这种猪不会受到以前由天然抗Gal抗体引起的严重排斥反应的影响。我们使用这些动物作为捐赠者的初步研究表明，与依赖慢性免疫抑制相比，受者狒狒接受旨在诱导T细胞耐受的方案时，维持生命的肾移植的存活率显著提高。在这个项目期间，我们扩大了跨越猪到狒狒屏障的耐受诱导的研究，并在几个方案中实现了灵长类抗猪反应性的特异性丧失，支持了耐受诱导的可行性。然而，在异种移植应用于临床之前，仍存在一些重大问题。这一重新提交的申请结合了四个组成部分的项目，涵盖了该研究领域最紧迫的问题和最有希望的方法：1)通过血管胸腺移植诱导耐受；2)通过混合嵌合体诱导耐受；3)利用人类免疫系统对小鼠的耐受进行建模；以及4)异种移植的血栓调节障碍。所有这些项目都是高度互动的，并利用了大量的共享资源，其中许多将通过大小动物的核心提供。这项工作将在一个独特的环境中进行，该环境为从事基础和细胞免疫学工作的科学家以及致力于将新疗法应用于临床的临床医生提供互动。

DESCRIPTION (provided by applicant): Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs. A major advance in organ xenograft survival has been the development of a knock-out strain of miniature swine (GalT-KO), which are not subject to the severe rejection previously caused by natural anti- Gal antibodies. Our initial studies using these animals as donors demonstrated a marked improvement in the survival of life-supporting renal transplants when recipient baboons were treated with a regimen designed to induce T cell tolerance, as compared to relying on chronic immunosuppression. During this project period, we have expanded our studies of tolerance induction across the pig-to-baboon barrier and have achieved specific loss of primate anti-pig reactivity in several protocols, supporting the feasibility of tolerance induction. Nevertheless, significant problems remain before xenotransplantation will be applicable clinically. This resubmission application combines four component projects that encompass the most pressing problems and the most promising approaches 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; and 4) 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 and small animal cores. The work will be carried out in a unique environment, which provides interactions among scientists working in basic and cellular immunology as well as with clinicians committed to taking new therapies to clinical applications.