Chronic Lung Allograft Rejection in MHC-Defined Swine

慢性排斥反应引起的移植物损失不同程度地影响所有实体器官，已成为肺移植长期成功的主要障碍。我们建立了一个大型的慢性肺排斥动物模型，该模型具有保真性和一致性，再现了人类肺移植受者慢性排斥的病理病变。基于初步数据和人体研究，我们假设慢性肺排斥反应是由T细胞对主要和次要组织相容性抗原的识别驱动的免疫介导过程。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。本提案的目的是验证这一假设，并在此过程中，研究慢性肺排斥过程的免疫机制。利用MHC近交系微型猪、合成多态性异体肽和猪T细胞交叉反应的单克隆抗体，我们计划：(1)确定慢性肺同种异体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肽的间接异体识别在微型猪慢性肺排斥反应发展中的作用和机制。(3)确定共刺激分子在微型猪慢性肺排斥发病机制中的作用。这些研究应该在临床相关的实验模型中更好地理解慢性肺排斥反应的细胞和分子机制，并可能最终导致开发新的策略来预防或治疗这种疾病。

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.