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)

• 批准号: 8956978
• 负责人: THALACHALLOUR MOHANAKUMAR
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956978
• 关键词: Allogenic; Allograft Tolerance; Alveolar Macrophages; Antibodies; Antigens; Ants; Autoantigens; Autoimmunity; Binding; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; Chronic; Chronic Disease; Clinical; Collagen; Cytoplasmic Granules; Detection; Development; Diagnosis; Disease; Disease model; Endothelial Cells; Epithelial; Epithelial Cells; Epitopes; Event; Gene Targeting; 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-17; Interleukin-6; Isoantibodies; Lead; Ligation; Lung; Lung Transplantation; Lung diseases; MHC Class I Genes; MHC binding peptide; Mediating; Membrane; Modeling; Molecular; Mus; Neutrophil Infiltration; Neutrophilia; Nuclear; Organ; Pathogenesis; Pathology; Phenotype; Play; Population; Property; RNA Interference; Reaction; Reagent; Regulatory T-Lymphocyte; Role; Seminal; Staging; Surface; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Translating; Transplantation; Tubulin; allograft rejection; base; crosslink; immunogenic; immunogenicity; lung allograft; macrophage; neutrophil; novel; novel therapeutics; pre-clinical; prevent; protective effect; protein expression; public health relevance; receptor; research study; response

 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可行治疗选择。不幸的是，肺移植物的长期存活和功能受到慢性排斥反应的限制，慢性排斥反应在临床上被诊断为闭塞性细支气管炎综合征（BOS），这是一种对治疗无反应的不可逆疾病，通常是致命的。利用新开发的闭塞性气道疾病（OAD）模型，我们证明了MHC和肺自身抗原（Ag）（Kα1微管蛋白（Kα 1 T）和胶原V（Col-V））抗体（Ab）在诱导对自身Ag和MHC的细胞和体液免疫应答中的重要作用，导致OAD。被动给予Ab导致诱导参与T辅助细胞（Zbtb 7a）、炎症级联（Laptm 5）和限制性调节性T细胞群（Mt 1）的活化的几种重要分子。我们使用同基因和同种异体鼠单LTx模型的结果表明，将Ab给予肺Ag可导致OAD。此外，我们有证据表明，抗MHC抗体以及抗Kα 1 T或Col-V抗体可以破坏对肺同种异体移植物的耐受性，导致在MHC错配LTx模型中的OAD，其中使用共刺激阻断建立耐受性。抗K α 1 T抗体不仅引起细胞自身免疫，而且引起细胞和体液对Col-V和供体MHC的反应，表明肺移植排斥反应中免疫反应的扩散。这些结果共同证明了抗MHC抗体和自身抗原在OAD发病机制中的重要作用。该项目的目标是：1）使用基于RNA干扰的靶向基因敲低来定义在导致T辅助细胞、炎性级联和T调节细胞活化的Ab施用后的早期事件，2）定义抗MHC和抗肺自身Ag诱导外泌体形成的机制，并定义外泌体在免疫应答扩散中的作用。我们证明，在给予Ab以及抗MHC（DSA）+人LTx受体后，来自小鼠的支气管肺泡灌洗液（BAL）在局部环境中含有浓度增加的外泌体，其表达肺自身Ag（Kα 1 T、Col-V和Col-I）。我们的假设是，这些外来体在引发增强的免疫应答中起着重要作用，导致分子间扩散，耐受性破坏和同种异体移植排斥。为此，我们将从BAL液中分离和表征外来体，并确定用外来体免疫是否调节刺激自身免疫和同种免疫应答的巨噬细胞表型的极化和转换，以及3）确定中性粒细胞在鼠LTx中Ab诱导的外来体形成中的作用。本提案的总体目标是采用独特的OAD临床前小鼠模型来描述导致人LTx后BOS发病机制中自身免疫的分子机制，并开发新的预防和/或治疗慢性肺移植排斥反应的治疗策略。