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（由应用提供）：肺移植（LTX）是终末期肺部疾病的可行治疗选择。不幸的是，肺合金的长期生存和功能受到慢性排斥的发展的限制，慢性排斥反应被临床诊断为细支气管炎闭塞症综合征（BOS），这是一种不可逆的对治疗无反应的疾病，通常是致命的。使用新开发的闭塞气道疾病模型（OAD），我们证明了对MHC的抗体（ABS）和肺自我抗原（AGS）（Kα1微管蛋白（Kα1T）和胶原蛋白V（Col-V）（COL-V））的第二个作用，诱导了细胞和体液上的免疫剂，从而使自我免疫剂促进了自我的免疫剂，从而引起了自我自我抗体和MHC和MHC。 ABS的被动施用导致诱导参与T辅助细胞激活（ZBTB7A），炎症级联反应（LAPTM5）和限制调节T细胞群（MT1）的几个重要分子。我们使用合成和同种型鼠单LTX模型的结果表明，对ABS的施用对肺AGS可以导致OAD。此外，我们还有证据表明，对MHC的ABS以及对Kα1T或Col-V的ABS可以破坏对肺合金的耐受性，导致在MHC不匹配的LTX模型中，使用共同刺激性阻断建立了公差。抗Kα1T的给药不仅会导致细胞自身免疫性对Kα1T，还导致细胞以及对Col-V和供体MHC的体液反应，表明肺同种异体移植排斥中免疫调查员的扩散。这些结果共同证明了ABS对MHC和自我在OAD发病机理中的重要作用。该项目的目标是：1）定义ABS给药后的早期事件，该事件会导致T辅助细胞，炎症级联反应和T调节细胞使用RNA干扰基于基于基于的靶向基因敲低的基因敲低，2）来定义抗MHC和抗肺自动体诱导外osemome形成和抗肺动物的机制，并在exosomes中诱导Exosome的作用，并在不受欢迎的情况下进行了侵蚀。我们证明，在给药ABS以及抗MHC（DSA）+人LTX受体后，来自小鼠的支气管肺泡灌洗（BAL）烟道包含局部环境中的外泌体浓度增加，这些环境表达肺自我自我（Kα1T，col-v和col-i）。我们的假设是，这些外泌体在引起增强免疫调查中起着至关重要的作用，导致分子间扩散，耐受性破坏和同种异体移植排斥。在此方面，我们将隔离和表征来自BAL液的外泌体，并确定外泌体免疫抑制是否调节巨噬细胞表型的极化和转换，从而刺激自身免疫和同种免疫反应，以及3）确定中性粒细胞在AB诱导的exosomes诱导的中性粒细胞中的作用。该提案的总体目标是采用OAD的独特临床前鼠模型来描述人类LTX后BOS发病机理的分子机制，并在人类LTX后发病，并制定新的治疗策略，以防止和/或治疗慢性肺Allocaft Allocaft Repottion。