Viral Pathogenesis in Xenotransplantation

异种移植中的病毒发病机制

• 批准号: 7790540
• 负责人: Jay A. Fishman
• 金额: $ 32.79万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7790540
• 关键词: Address; Age; Allografting; Animal Model; Animals; Antibodies; Area; BK Virus; Biological Assay; Biology; Biopsy Specimen; Blood Coagulation Disorders; Cell Communication; Cells; Clinical; Clinical Trials; Collaborations; Complement; Cross Reactions; Cytomegalovirus; DNA; Data; Development; Endogenous Retroviruses; Epitopes; Excision; Exclusion; Family; Family suidae; Future; Gagging; Galactosyltransferases; Generations; Genes; Genetic Recombination; Germ Lines; Goals; Graft Rejection; Graft Survival; Haplotypes; Hematopoietic; Herpesviridae; Human; Human Cell Line; Immune; Immune Tolerance; Immunity; Immunoglobulin Joining Region; Immunologics; In Vitro; Infection; Infection Control; Investigation; Laboratories; Measurement; Measures; Messenger RNA; Miniature Swine; Modeling; Molecular; Mus; Organ; Organism; Papio; Pathogenesis; Peripheral Blood Mononuclear Cell; Plasmids; Post-Translational Protein Processing; Pre-Clinical Model; Primates; Principal Investigator; Production; Proviruses; Recombinants; Relative (related person); Resistance; Retroviridae; Retroviridae Infections; Risk; Role; Series; Serum; Skin Transplantation; Skin graft; Solutions; Testing; Thymus Gland; Tissues; Transplant Recipients; Transplantation; Viral; Viral Antigens; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Xenograft procedure; clinical application; immunoregulation; in vivo; latent infection; novel; pathogen; programs; receptor; receptor expression; recombinant virus; respiratory virus; response

Xenotransplantation has been proposed as a solution to the shortage of human organs available for transplantation. The recent availability of inbred miniature swine with homozygous disruption of the a- galactosyltransferase genes (GalT-KO) has enhanced the likelihood that immunologic hurdles to pig-to- primate Xenotransplantation may be overcome. Concerns regarding the clinical application of Xenotransplantation have focused on the risk of infection due to novel organisms from non-human species in xenograft recipients. While no such xenogeneic infections have been identified in humans exposed to pig tissues, previous studies have identified a series of viral pathogens of swine activated within porcine xenografts. These include the family of porcine endogenous retroviruses (PERV) first cloned in this laboratory, as well as porcine cytomegalovirus (PCMV) and porcine lymphotropic herpesvirus (PLHV-1). The goal of this proposal is to examine the risk for infection of primates by porcine pathogens undergoing Xenotransplantation. In particular, we will study the mechanisms underlying production of human-tropic recombinant PERV A-C, xenografts from GalT-KO swine, and the impact of viral infections on graft survival. These studies will utilize long-standing collaborations with on-going studies of tolerance induction across species' barriers in primate and murine models. These studies will extend observations on xenogeneic infections in three areas. Specific Aim 1: To characterize mechanisms for the generation of human-tropic recombinant porcine endogenous retrovirus (PERV A-C) and the effects on virus production of tolerance induction strategies. Specific Aim 2: To determine whether the risk of infection by porcine endogenous retrovirus for primates and human cells, if any, is increased using xenografts from GalT-KO swine. Specific Aim 3: To assess the role of other viral infections on graft survival and PERV production in Xenotransplantation. These data will examine molecular and cellular mechanisms associated with the production of potential human pathogens and may allow the exclusion of these pathogens from miniature swine used in future clinical trials.

已提出异种移植作为解决可用于人类器官短缺的解决方案 移植。近交微型猪最近的可用性，纯合破坏了A- 半乳糖基转移酶基因（Galt-KO）增强了免疫学障碍到猪至猪的可能性 灵长类动物的异种移植可以克服。关于临床应用的担忧 异种移植的重点是由于非人类物种的新生物而引起的感染风险 在异种移植受体中。虽然在暴露于猪的人类中尚未发现这种异构感染 组织，以前的研究已经确定了一系列在猪内激活的猪病毒病原体 异种移植物。其中包括首先克隆的猪内源性逆转录病毒（PERV）家族 实验室以及猪巨细胞病毒（PCMV）和猪淋巴疱疹病毒（PLHV-1）。 该提案的目的是检查猪病原体感染灵长类动物的风险 进行异种移植。特别是，我们将研究基本机制 生产人类效率重组PERV A-C，Galt-KO猪的异种移植物，以及 病毒感染对移植物存活的影响。这些研究将利用与 在灵长类动物和鼠模型中，正在进行的关于物种障碍跨种类耐受性的研究。这些 研究将扩展对三个地区异种感染的观察。特定目的1：要描述 生成人类糖重组猪内源性逆转录病毒（PERV A-C）的机制 以及对耐受诱导策略的病毒产生的影响。特定目标2：确定是否 猪内源性逆转录病毒对灵长类动物和人类细胞（如果有）感染的风险增加 使用来自Galt-Ko猪的异种移植物。特定目的3：评估其他病毒感染对移植的作用 异种移植中的生存和生产。这些数据将检查分子和细胞 与潜在人类病原体的产生相关的机制，并可能排除 这些病原体来自未来临床试验中使用的微型猪。