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: 6901859
• 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/6901859
• 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.

慢性排斥反应的移植损失在不同程度上影响所有固体器官，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，该模型以忠诚度和一致性（人类肺部肺移植受体中看到的病理性病变）繁殖，患有慢性抑制。 基于初步数据和人类研究，我们假设慢性肺排斥是由主要和较小的组织相容性抗原识别的免疫学介导的过程。 该假设的推论是，下调免疫系统或诱导免疫耐受性的方案最有效地预防，中断和/或反向慢性肺部排斥。 该提案的目的是检验这一假设，并在此过程中研究慢性肺部排斥过程的免疫机制。使用MHC含杂交微型猪，合成多态性异肽和单克隆抗体对猪T细胞的交叉反应性，我们计划（1）定义慢性肺同种异体移植抑制的免疫原性要求，并表征该疾病的作用和机制，（2）介导了该疾病的作用，（2）在微型猪中慢性肺排斥的发展中，（3）确定了刺激性分子在微型猪中慢性肺排斥的发病机理中的作用。 这些研究应更好地了解临床相关的实验模型中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该疾病的新策略。

项目成果

The role of indirect recognition of MHC class I and II allopeptides in a fully mismatched miniature swine model of lung transplantation.

MHC I 类和 II 类同种肽在完全不匹配的小型猪肺移植模型中间接识别的作用。

• DOI: 10.1016/j.transproceed.2006.10.059
• 发表时间: 2006
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Sahara,H;Shoji,T;Ng,CY;Weiss,MJ;Muniappan,A;Guenther,DA;Houser,SL;Pujara,AC;Sayre,JK;Wain,JC;Sachs,DH;Madsen,JC;Allan,JS
• 通讯作者: Allan,JS

Thymectomy does not abrogate long-term acceptance of MHC class I-disparate lung allografts in miniature Swine.

胸腺切除术不会取消小型猪对 MHC I 类不同同种异体肺移植物的长期接受。

• DOI: 10.1016/j.transproceed.2006.10.064
• 发表时间: 2006
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Sahara,H;Weiss,MJ;Ng,CY;Houser,SL;Pujara,AC;Sayre,JK;Wain,JC;Sachs,DH;Madsen,JC;Allan,JS
• 通讯作者: Allan,JS

An MHC class II disparity raises the threshold for tolerance induction in pulmonary allografts in miniature swine.

MHC II 类差异提高了小型猪同种异体肺移植耐受诱导的阈值。

• DOI: 10.1016/j.transproceed.2006.10.161
• 发表时间: 2006
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Shoji,T;Sahara,H;Muniappan,A;Guenther,DA;Houser,SL;Pujara,AC;Bravard,MA;Wain,JC;Sachs,DH;Madsen,JC;Allan,JS
• 通讯作者: Allan,JS

Operational tolerance to class I disparate lungs can be induced despite pretransplant immunization with class I allopeptides.

尽管使用I类同种肽进行移植前免疫，但仍可诱导对I类不同肺的操作耐受性。

• 发表时间: 2007
• 期刊: Transplantation 84(11)
• 作者: Shoji T;Sahara H;Muniappan A;Guenther DA;Wain JC;Houser SL;Bravard MA;Pujara AC;Hasse RS;Sachs DH;Madsen
• 通讯作者: Madsen