Non-Human primate models for human xenotransplantation

描述(改编自申请者的摘要)：这项建议的长期目标是了解导致 异种移植的排斥反应和开发新的治疗策略 防止这种反应。在目前的申请中，调查人员已经 选择重点研究恒河猴异种移植反应的体液成分 猴子作为他们在人类身上进行的初步研究表明 对异种移植物的抗体反应是由有限的人群编码的 生殖系免疫球蛋白基因。申请者最近假设 介导快速免疫的异种反应性抗体和天然抗体 对感染性病原体的反应在结构和功能上是相关的， 都是由B细胞产生的，而不需要T细胞的帮助。 调查人员对此应用程序的直接目标是下一个 在实现其长远目标的一步中，是验证使用 猕猴作为测试新方法和新方法的实验模型 预防这些早期体液疾病的治疗策略 患者的异种移植排斥反应。东半球灵长类动物的使用目前 科学价值有限，因为几乎没有可用的直接信息 关于这些物种对异种猪移植的宿主免疫反应的性质。 该提案的具体目标包括直接比较免疫球蛋白基因。 负责编码异种抗体反应，确定是否相同 抗体群体被用来调节对分离的细胞和 带血管的器官移植，以及哪些B细胞亚群被用来产生 新的异种抗体。国家卫生政策是最后和强制性的步骤 新的治疗策略在人体临床试验和工作中的应用 本建议书中描述的内容直接说明了 实验模型。了解负责机制的基础 对于NHP中的异种移植排斥反应是至关重要的：1)使用这种 实验模型作为新药候选预防的测试平台 异种移植引入患者前的排斥反应；2) 开发新的治疗策略以延长异种移植物的存活时间 将不可能直接在患者身上进行测试，以及3)新的 灵长类动物异种移植反应性质的基本信息。

DESCRIPTION (Adapted from the applicant's abstract): The long-range objective of this proposal is to understand the immunological pathways responsible for the rejection of xenografts and to develop new therapeutic strategies to prevent this reaction. In the current application, the investigators have chosen to focus on the humoral components of the xenograft reaction in rhesus monkeys as preliminary work they have conducted in humans has demonstrated that antibody responses to xenografts are encoded by a restricted population of germline Ig genes. The applicants have recently hypothesized that xenoreactive antibodies and natural antibodies that mediate rapid immune responses to infectious agents are structurally and functionally related and are both produced by B cells independent of a requirement for T cell help. The investigators' immediate objective for this application, which is the next step in the attainment of their long-range goal, is to validate the use of rhesus monkeys as an experimental model for testing new approaches and treatment strategies for preventing these early phases of the humoral xenograft rejection in patients. The use of Old World primates is currently of limited scientific value as there is almost no direct information available on the nature of the host immune reaction in these species to pig xenografts. The specific aims of the proposal include a direct comparison of the Ig genes responsible for encoding the xenoantibody response, establishing if identical populations of antibodies are used to mediate rejection of isolated cells and vascularized organ grafts, and which subsets of B cells are used to produce new xenoantibodies. NHPs represent a final and obligatory step in the application of new treatment strategies to human clinical trials and the work described in this proposal directly addresses the usefulness of this experimental model. Understanding the basis for the mechanisms responsible for xenograft rejection in NHPs is critical for: 1) the use of this experimental model as a testing platform for new drug candidates to prevent xenograft rejection prior to their introduction into patients; 2) the development of new therapeutic strategies to prolong xenograft survival that would be impossible to test directly in patients, and 3) the generation of new fundamental information of the nature of the xenograft response in primates.