ALLOANTIBODIES TO MHC INDUCES AUTOIMMUNITY AND OBLITERATIVE AIRWAY DISEASE (OAD)

MHC 同种抗体可诱发自身免疫和闭塞性气道疾病 (OAD)

基本信息

批准号：
9265488
负责人：
THALACHALLOUR MOHANAKUMAR
金额：
$ 37.84万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265488
关键词：
Allogenic Allograft Tolerance Alveolar Macrophages Antibodies Antigen Presentation Antigens Ants Autoantigens Autoimmunity Binding Bronchiolitis Obliterans Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes Candidate Disease Gene Cells Chronic Clinical Collagen Cytoplasmic Granules Detection Development Disease Disease model Endothelial Cells Epithelial Cells Epitopes Event Gene Targeting Genetic Transcription Goals Helper-Inducer T-Lymphocyte Human Immune Immune response Immune system Immunization Immunologics In Vitro Inbred BALB C Mice Infiltration Inflammation Mediators Inflammatory Injury Interleukin 6 Receptor Interleukin-17 Interleukin-6 Isoantibodies Lead Ligation Lung Lung Transplantation Lung diseases MHC Class I Genes Mediating Membrane Modeling Molecular Mus Neutrophil Infiltration Neutrophilia Nuclear Organ Pathogenesis Peptides Pharmacology Phenotype Play Population Property Pulmonary Pathology RNA Interference Reagent Regulatory T-Lymphocyte Respiratory physiology Role Seminal Surface Syndrome T-Cell Activation T-Lymphocyte Testing Translating Tubulin allograft rejection base clinical Diagnosis crosslink exosome experimental study immunogenic immunogenicity immunoreaction knock-down lung allograft macrophage mouse model neutrophil novel novel therapeutic intervention pre-clinical prevent protective effect protein expression public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Lung transplantation (LTx) is a viable treatment option for end-stage pulmonary diseases. Unfortunately long-term survival and function of lung allografts is limited by development of chronic rejection that is clinically diagnosed as bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy and often fatal. Using newly developed models of obliterative airway disease (OAD), we demonstrated a seminal role for antibodies (Abs) to MHC and to lung self-antigens (Ags) (Kα1 Tubulin (Kα1T) and Collagen V (Col-V)) in inducing cellular and humoral immune responses to self-Ags and MHC leading to OAD. Passive administration of Abs resulted in induction of several important molecules involved in the activation of T helper cells (Zbtb7a), inflammatory cascade (Laptm5) and limiting regulatory T cell populations (Mt1). Our results using syngeneic and allogenic murine single LTx models have demonstrated that administration of Abs to lung Ags can lead to OAD. Further, we have evidence that Abs to MHC as well as Abs to Kα1T or Col-V can break tolerance to lung allografts resulting in OAD in a MHC mismatch LTx model in which tolerance was established using co-stimulatory blockade. Administration of anti-Kα1T resulted in not only cellular autoimmunity to Kα1T but also cellular as well as humoral responses to Col-V and donor MHC indicating spreading of immune responses in lung allograft rejection. These results collectively demonstrate an important role for Abs to MHC and self-Ags in the pathogenesis of OAD. The goals of this project are to: 1) define the early events following administration of Abs that leads to activation of T helper cells, inflammatory cascade, and T regulatory cells using RNA interference based targeted gene knockdown, 2) to define the mechanisms by which anti-MHC and anti-lung self-Ags induce exosome formation and define the role of exosomes in the spreading of immune responses. We demonstrated that bronchoalveolar lavage (BAL) fluids from mice following administration of Abs as well as anti-MHC (DSA)+ human LTx recipients contain increased concentration of exosomes in the local milieu, which express lung self-Ags (Kα1T, Col-V and Col-I). Our hypothesis is that these exosomes play an essential role in eliciting augmented immune responses leading to intermolecular spreading, breaking of tolerance and allograft rejection. Towards this we will isolate and characterize exosomes from BAL fluid and determine if immunization with exosomes regulates the polarization and switch in macrophage phenotypes that stimulates auto-immune and alloimmune responses, and 3) determine the role of neutrophils in the Ab induced exosome formation in murine LTx. The overall goal of this proposal is to employ unique preclinical murine models of OAD to delineate the molecular mechanisms leading to autoimmunity in the pathogenesis of BOS following human LTx and to develop new therapeutic strategies towards preventing and/or treating chronic lung allograft rejection.

描述（由申请人提供）：肺移植（LTx）是终末期肺部疾病的一种可行的治疗选择，不幸的是，同种异体肺移植物的长期存活和功能受到临床诊断为闭塞性细支气管炎综合征的慢性排斥反应的限制。 BOS）是一种对治疗无反应且通常致命的不可逆疾病。使用新开发的闭塞性气道疾病（OAD）模型，我们证明了抗体的重要作用。 (Abs) 到 MHC 和肺自身抗原 (Ags)（Kα1 微管蛋白 (Kα1T) 和胶原蛋白 V (Col-V)），诱导对自身 Ags 和 MHC 的细胞和体液免疫反应，从而导致 OAD 的被动施用。导致几种重要分子的诱导，这些分子参与 T 辅助细胞 (Zbtb7a) 的激活、炎症级联 (Laptm5) 和限制调节性 T 细胞群(Mt1)。我们使用同基因和同种异体小鼠单一 LTx 模型的结果表明，给予肺 Ag 抗体可导致 OAD。此外，我们有证据表明，MHC 抗体以及 Kα1T 或 Col-V 抗体可破坏耐受性。肺同种异体移植导致 MHC 不匹配 LTx 模型中的 OAD，其中使用共刺激阻断建立耐受性，施用抗 Kα1T 不仅导致细胞自身免疫。 Kα1T 以及对 Col-V 和供体 MHC 的细胞和体液反应表明免疫反应在肺同种异体移植排斥中扩散。这些结果共同证明了针对 MHC 的抗体和自身抗原在 OAD 发病机制中的重要作用。该项目的目的是：1) 使用基于 RNA 干扰的靶向基因敲除来定义注射 Abs 后导致 T 辅助细胞、炎症级联和 T 调节细胞激活的早期事件，2) 定义抗 MHC 和抗肺自身抗原诱导外泌体形成，并确定了外泌体在免疫反应传播中的作用，我们证明了给予 Ab 和抗 MHC (DSA) 后小鼠的支气管肺泡灌洗 (BAL) 液。 + 人类 LTx 受体的局部环境中外泌体浓度增加，这些外泌体表达肺自身 Ag（Kα1T、Col-V 和 Col-I）。为此，我们将从 BAL 液体中分离和表征外泌体，并确定外泌体免疫是否调节刺激自身的巨噬细胞表型的极化和转换。免疫和同种免疫反应，以及3)确定中性粒细胞在Ab诱导的小鼠LTx外泌体形成中的作用该提案的总体目标是采用独特的方法。 OAD 的临床前小鼠模型，用于描绘人类 LTx 后 BOS 发病机制中导致自身免疫的分子机制，并开发新的治疗策略，预防和/或治疗慢性肺同种异体移植排斥。