A TOLERANCE APPROACH TO XENOTRANSPLANTATION

异种移植提供了最好的近期希望，以满足目前身体同种异体器官严重短缺对移植领域施加的关键限制。我们在本项目资助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为单位衡量，而不是以天为单位。提高存活率的一个主要因素是发展了一种新的小型猪基因敲除品系(Galt-KO)，它不在细胞上表达Gal表位，从而避免了以前由天然抗Gal抗体引起的严重排斥反应。我们还表明，使用这些新的捐赠者，器官存活率的最大改善是使用旨在诱导耐受的方案。然而，在这项技术准备好临床应用之前，还需要进一步的改进。这一新的应用汇集了五个项目，这些项目致力于该研究领域最有前途的方法和最紧迫的问题：1)通过带血管胸腺移植诱导耐受；2)通过混合嵌合体诱导耐受；3)利用人类免疫系统建立小鼠耐受模型；4)异种移植中的病毒发病机制；以及5)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，其中许多将通过大型动物核心提供。这项工作将在一个独特的环境中进行，提供与同一研究中心从事基础和细胞免疫学以及相关小动物和大动物模型工作的科学家的互动，以及与致力于将新疗法应用于临床的临床医生的互动。

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.