Chronic Lung Allograft Rejection in MHC-Defined Swine

MHC 定义的猪的慢性肺同种异体移植排斥

• 批准号: 6437219
• 负责人: James S. Allan
• 金额: $ 32.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6437219
• 关键词: MHC class I antigen; MHC class II antigen; RNase protection assay; antigen presenting cell; biopsy; cellular immunity; chronic disease /disorder; cyclosporines; cytokine; cytotoxic T lymphocyte; flow cytometry; gene expression; helper T lymphocyte; homologous transplantation; humoral immunity; immunosuppression; intermolecular interaction; isoantibody; lung transplantation; major histocompatibility complex; miniature swine; monoclonal antibody; pathologic process; polymerase chain reaction; terminal nick end labeling; transplant rejection; transplantation immunology

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.

慢性排斥反应导致的移植物损失，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。 我们建立了慢性肺排斥的大型动物模型，该模型保真度和一致性地再现了患有慢性排斥的人类肺移植受者中观察到的病理病变。 根据初步数据和人体研究，我们假设慢性肺排斥是由 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/或逆转慢性肺部排斥反应。 该提案的目的是检验这一假设，并在此过程中研究慢性肺排斥过程背后的免疫机制。使用 MHC 近交小型猪、合成多态性同种肽和与猪 T 细胞交叉反应的单克隆抗体，我们计划 (1) 定义慢性肺同种异体移植排斥的免疫遗传学要求，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，以及（3）确定共刺激的作用小型猪慢性肺排斥反应发病机制中的分子。 这些研究应该有助于更好地了解临床相关实验模型中慢性肺排斥的细胞和分子机制，并可能最终导致开发预防或治疗这种疾病的新策略。