Chronic Lung Allograft Rejection in MHC-Defined Swine

慢性排斥反应导致的移植物丢失，不同程度地影响到所有实体器官，已成为肺移植长期成功的主要障碍。我们已经建立了一个大型的慢性肺排斥动物模型，它能逼真和一致地复制出患有慢性排斥反应的人肺移植受者的病理损害。根据初步数据和人类研究，我们假设慢性肺排斥是由T细胞对主要和次要组织相容性抗原的识别所驱动的免疫学过程。这一假设的推论是，下调免疫系统或诱导免疫耐受的方案将最有效地预防、中断和/或逆转慢性肺排斥反应。这项建议的目的是验证这一假设，并在此过程中，研究慢性肺排斥反应过程的免疫学机制。利用MHC近交系小型猪、人工合成的多态别肽和与猪T细胞发生交叉反应的单抗，我们计划(1)确定慢性肺移植排斥反应的免疫遗传学要求，并表征介导这种疾病的细胞和体液机制；(2)研究供体MHC多肽在小型猪慢性肺排斥反应中的作用和机制；以及(3)确定共刺激分子在小型猪慢性肺排斥反应发病机制中的作用。这些研究将有助于在临床相关的实验模型中更好地理解慢性肺排斥的细胞和分子机制，并最终可能导致开发预防或治疗这种疾病的新策略。

Graft loss from chronic rejection, which affects all solid organs to varying degrees, has become the major obstacle to the long-term success of lung transplantation. We have established a large animal model of chronic lung rejection, which reproduces with fidelity and consistency, the pathological lesions seen in human lung transplant recipients suffering from chronic rejection. Based on preliminary data and human studies, we hypothesize that chronic lung rejection is an immunologically mediated process driven by T cell recognition of major and minor histocompatibility antigens. The corollary to this hypothesis is that protocols to downregulate the immune system or to induce immune tolerance will most effectively prevent, interrupt and/or reverse chronic lung rejection. The goal of this proposal is to test this hypothesis and, in doing so, investigate the immunologic mechanisms underlying the process of chronic lung rejection. Using MHC inbred miniature swine, synthetic polymorphic allopeptides, and monoclonal antibodies cross-reactive for swine T cells, we plan to (1) define the immunogenetic requirements of chronic lung allograft rejection and characterize the cellular and humoral mechanisms that mediate this disease, (2) examine the role and mechanisms of indirect allorecognition of donor MHC peptides in the development of chronic lung rejection in miniature swine, and (3) determine the role of costimulatory molecules in the pathogenesis of chronic lung rejection in miniature swine. These studies should lead to a better understanding of the cellular and molecular mechanisms of chronic lung rejection in a clinically relevant experimental model and may ultimately lead to the development of new strategies to prevent or treat this disease.