A Tolerance Approach to Xenotransplantation

描述（由申请人提供）：异种移植仍然是近期缓解同种异体器官严重短缺的最佳希望。器官异种移植存活的一个重大进展是一种微型猪的敲除菌株（GalT-KO）的发展，它不会受到以前由天然抗Gal抗体引起的严重排斥反应。我们使用这些动物作为供体的初步研究表明，与依赖慢性免疫抑制相比，当受体狒狒接受旨在诱导T细胞耐受性的方案治疗时，维持生命的肾移植的存活率显着提高。在本项目期间，我们扩大了对猪-狒狒屏障耐受诱导的研究，并在几个方案中实现了灵长类动物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。本次申请由四个组成部分组成，涵盖了该领域研究中最紧迫的问题和最有前途的方法：1)通过血管化胸腺移植诱导耐受；2)混合嵌合诱导耐受性；3)建立具有人类免疫系统的小鼠耐受性模型；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，其中许多将通过大大小小的动物核心提供。这项工作将在一个独特的环境中进行，这将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.