Chronic Lung Allograft Rejection in MHC-Defined Swine

慢性排斥反应导致的移植物丢失已成为影响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反应的动物模型，再现与保真度和一致性，病理病变中看到的人肺移植受体遭受慢性排斥反应。 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细胞识别主要和次要组织相容性抗原驱动的免疫介导的过程。 该假设的推论是，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。 本研究的目的是验证这一假说，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、合成的多态性同种异体肽和与猪T细胞交叉反应的单克隆抗体，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）检查供体MHC肽的间接同种异体识别在小型猪慢性肺排斥反应发展中的作用和机制，（3）探讨共刺激分子在小型猪慢性肺排斥反应发病机制中的作用。 这些研究应该导致更好地了解慢性肺排斥反应的细胞和分子机制在临床相关的实验模型，并可能最终导致新的策略，以预防或治疗这种疾病的发展。

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.