A Tolerance Approach to Xenotransplantation

异种移植的耐受方法

基本信息

批准号：
8499187
负责人：
DAVID H SACHS
金额：
$ 276.18万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499187
关键词：
Adenosine Allogenic Animals Antibodies Australia Binding CD47 gene Cell physiology Cells Cellular Immunology Chimerism Chronic Collaborations Commit Communicable Diseases Communication Cytomegalovirus Development Disease Engraftment Environment Evaluation Family suidae Genetic Goals Housing Human Immune Immune Tolerance Immune response Immune system Immunodeficient Mouse Immunosuppression Inbreeding Infection Institutes Kidney Kidney Diseases Kidney Transplantation Knock-out Life Maintenance Miniature Swine Modeling Mus Natural Killer Cells Organ Organ Transplantation Papio Prevention strategy Primates Production Program Research Project Grants Progress Reports Proteinuria Protocols documentation Quality Control Reagent Regimen Regulatory T-Lymphocyte Research Research Personnel Resource Sharing Role Scientist Surface Antigens System T-Lymphocyte Technology Testing Thrombomodulin Thymus Gland Transgenic Animals Transgenic Organisms Transplantation Transplantation Tolerance Up-Regulation Work Xenograft procedure bone clinical application design in vivo innovation macrophage man mouse model nonhuman primate programs public health relevance receptor reconstitution

项目摘要

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.

描述（由申请人提供）：异种移植仍然是缓解同种异体器官严重短缺的近期最佳希望。器官异种移植存活的一个重大进展是小型猪基因敲除品系(GalT-KO)的开发，该品系不会遭受先前由天然抗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 细胞耐受的方案治疗时，维持生命的肾移植的存活率显着提高。在这个项目期间，我们扩大了跨越猪与狒狒屏障的耐受诱导研究，并在多个方案中实现了灵长类动物抗猪反应性的特定丧失，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然存在重大问题。该重新提交申请结合了四个组成项目，涵盖了该研究领域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) 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和小型动物核心提供。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了互动。