A TOLERANCE APPROACH TO XENOTRANSPLANTATION

异种器官移植通常被认为是解决目前因尸体供体器官严重短缺而对移植领域造成的主要限制的最有可能的短期解决方案。由于各种原因，猪现在似乎是供体的选择，在这个实验室开发的小型猪有几个优势，作为潜在的异种移植供体。由于对这种不协调移植的免疫反应非常强烈，临床异种移植的成功可能至少部分依赖于找到诱导特异性低反应性或耐受性的方法，而不是完全依赖于非特异性免疫抑制。在本项目中，我们将利用大型动物猪到灵长类动物模型来研究和克服这种不协调异种移植的主要障碍，并将强调诱导耐受性作为该方法的主要部分。我们将专注于四个主要领域，每个领域都构成该计划组成部分拨款的基础：1)避免天然抗体的返回或其影响；2)在T细胞水平上产生持久的耐受性；3)避免异种移植后凝血病变；4)理解和管理与异种移植相关的潜在传染病问题。所有这些项目都是高度互动的，并利用了许多共享资源，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，它提供了与在同一研究中心从事基础和细胞免疫学工作的科学家以及从事相关小动物模型研究的科学家以及致力于将新疗法用于临床应用的临床医生的互动。

Xenotransplantation is generally considered the most likely near-term solution to the major limitation imposed on the field of transplantation today by the severe shortage of cadaver donor organs. For a variety of reasons, the pig now appears to be the donor species of choice, and miniature swine, developed in this laboratory, have several advantages as potential xenograft donors. Because the immune response to such discordant transplantation is exceedingly strong the success of clinical xenografting is likely to depend, at least in part, on finding ways of inducing specific hyporesponsiveness, or tolerance, rather than relying entirely on non-specific immunosuppression. In this Program Project grant we will utilize a large animal pig to primate model to study and overcome the major pediments to such discordant xenotransplantation, and will emphasize the induction of tolerance as a major part of the approach. We will concentrate on four major areas, each constituting the basis of a component grant of the program: 1) avoiding the return of natural antibodies or the effects thereof; 2) producing durable tolerance at the T Cell level; 3) avoiding coagulopathy following xenogeneic transplantation; and 4) understanding and managing the potential infectious disease problems associated with 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 animal models in the same research center, as well as with clinicians committed to taking new therapies to clinical applications.