Non-Human primate models for human xenotransplantation

描述（改编自申请人的摘要）：长期目标 这一建议的目的是了解免疫途径， 异种移植排斥反应，并开发新的治疗策略， 防止这种反应。 在目前的申请中，调查人员已经 选择的重点是恒河猴异种移植反应的体液成分 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一个有限的群体编码的 生殖系IG基因。 申请人最近假设， 异种反应性抗体和介导快速免疫的天然抗体 对感染因子的反应在结构上和功能上是相关的， 都是由B细胞产生的，不需要T细胞的帮助。 调查人员对这一应用程序的直接目标，这是下一个 实现其长期目标的一个步骤是验证 恒河猴作为测试新方法的实验模型， 预防这些体液免疫早期阶段的治疗策略 患者的异种移植排斥反应。 使用旧大陆灵长类动物目前是 科学价值有限，因为几乎没有直接的信息 这些物种对猪异种移植物的宿主免疫反应的性质。 该提案的具体目标包括直接比较IG基因 负责编码异种抗体应答，确定是否相同 抗体群用于介导分离细胞的排斥， 血管化的器官移植，以及B细胞的亚群用于产生 新的异种抗体 国家卫生方案是国家卫生政策的最后一步， 新治疗策略在人体临床试验中的应用 本建议中所描述的直接解决了这一有用性， 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至关重要：1）使用这种 实验模型作为新药候选物的测试平台， 异种移植物在引入患者体内之前发生排斥反应; 2） 开发新的治疗策略以延长异种移植物存活， 不可能直接在患者身上进行测试，3）新一代的 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.