Immunological Mechanisms in Systemic Autoimmune Disease

系统性自身免疫性疾病的免疫学机制

基本信息

批准号：
7527648
负责人：
Ann Marshak-Rothstein
金额：
$ 35.75万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-08 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7527648
关键词：
Accounting Activated Lymphocyte Activities of Daily Living Address Animal Model Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Antigens Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding Blood Vessels Cells Chimeric Proteins Chronic Clinical Complex Dendritic Cells Development Disease Disease Progression E-Cadherin Etiology Exhibits Fibrosis Goals Heart Immune system Immunoglobulin G Inbred BALB C Mice Individual Inflammatory Inherited Kidney Lead Life Lung MHC Class II Genes Membrane Modeling Monoclonal Antibodies Morbidity - disease rate Mus Mutation Nuclear Nuclear Antigens Nuclear Extract Organ Outcome Ovalbumin Patients Phenotype Predisposing Factor Protein Overexpression Public Health Research Serum Skin Skin Abnormalities Specificity Systemic Lupus Erythematosus Systemic Scleroderma T-Lymphocyte T-Lymphocyte Subsets TLR7 gene Tetracycline Tetracyclines Thinking Tissues Trans-Activators Transgenic Mice Transgenic Model Tumor Necrosis Factor Ligand Superfamily Member 6 Vascular Endothelium base fibrillin insight invariant chain mortality novel novel therapeutics promoter response

项目摘要

DESCRIPTION (provided by applicant): Systemic Sclerosis (SSc) can be a chronic life threatening autoimmune disorder associated with severe vascular damage and fibrosis of the skin and/or internal organs. Nevertheless, the factors that predispose individuals to the development of SSc, as opposed to other more common systemic autoimmune diseases such as SLE, remain ill-defined, and treatment options for patients afflicted with devastating forms of this disease are extremely limited. Intriguingly, although both SSc and SLE patients develop anti-nuclear antibodies (ANAs), each disease is associated with a distinct set of specificities that may reflect discrete aspects of tissue damage. Research in this area has been hampered by the lack of suitable animal models. We have recently developed a novel transgenic model that allows for the regulated expression of a "pseudo- autoantigen" on either MHC class II+ cells or on the vascular endothelium, and the potential for expression by other tissues known to be targeted in SSc. The overall goal of this application is to determine how specific T cell subsets and/or the microenvironment of pseudo-autoantigen expression influence the autoantibody repertoire and the clinical course of systemic autoimmune disease. The specific aims of the application are as follows: (1) Determine whether the autoantigens routinely associated with SSc can activate B cells and/or dendritic cells, and if so, whether they are preferentially released from tissues thought to be targeted by the immune system in SSc. (2) Determine how the functional capacity of "pseudo-autoantigen"- specific T cells influences the isotype and specificity of the autoantibody repertoire as well as the type of systemic autoimmune disease that is elicited in mice that systemically express the pseudo-autoantigen. (3) Determine how the microenvironment of pseudo-autoantigen expression influences the autoantibody repertoire and the type of systemic autoimmune disease that is elicited in mice by comparing the outcome of pseudo- autoantigen expression by MHC class II+ cells (conventional antigen presenting cells) to pseudo-autoantigen express by cells of the vascular endothelium. These studies will involve donor DO11 T cells, skewed to a Th1, Th2, or Th17 phenotype, and recipient mice that inherit (a) a tetracycline transactivator driven by either an invariant chain promoter or a vascular endothelial promoter and (2) a membrane-associated ovalbumin fusion protein whose expression is regulated by a tetracycline transactivator. T cells obtained from wildtype, lpr, or gld DO11 mice, will be included in the analysis since over-expression of FasL has been found to trigger a chronic fibrotic response in numerous experimental settings. Our results should provide important insights into the mechanistic basis of SSc and point to new therapeutic strategies for this devastating disease. PUBLIC HEALTH RELEVANCE: No proven treatment is currently available for many manifestations of Systemic Sclerosis (SSc), a devastating disease with significant morbidity and mortality. This study could lead to significant insights into the factors that trigger the development of SSc and strategies that might prove useful in limiting the progression of disease in afflicted patients.

描述（由申请人提供）：系统性硬化症（SSc）可能是一种慢性危及生命的自身免疫性疾病，与皮肤和/或内脏器官的严重血管损伤和纤维化相关。然而，与其他更常见的系统性自身免疫性疾病（如 SLE）相比，导致个体发生 SSc 的因素仍然不明确，而且患有这种破坏性疾病的患者的治疗选择也极其有限。有趣的是，尽管 SSc 和 SLE 患者都会产生抗核抗体 (ANA)，但每种疾病都与一组不同的特异性相关，这些特异性可能反映组织损伤的不同方面。由于缺乏合适的动物模型，该领域的研究受到阻碍。我们最近开发了一种新型转基因模型，该模型允许在 MHC II+ 类细胞或血管内皮上调节“假自身抗原”的表达，并有可能通过已知的 SSc 靶向的其他组织进行表达。本申请的总体目标是确定特定 T 细胞亚群和/或假自身抗原表达的微环境如何影响自身抗体库和系统性自身免疫性疾病的临床病程。该申请的具体目的如下：（1）确定通常与SSc相关的自身抗原是否可以激活B细胞和/或树突状细胞，如果可以，它们是否优先从被认为是免疫系统靶向的组织中释放出来在SSc。 (2) 确定“伪自身抗原”特异性 T 细胞的功能能力如何影响自身抗体库的同种型和特异性，以及在系统性表达伪自身抗原的小鼠中引发的系统性自身免疫性疾病的类型。 (3) 通过比较 MHC II+ 类细胞（传统抗原呈递细胞）与伪自身抗原表达的结果，确定伪自身抗原表达的微环境如何影响自身抗体库和在小鼠中引发的全身性自身免疫性疾病的类型-自身抗原由血管内皮细胞表达。这些研究将涉及偏向 Th1、Th2 或 Th17 表型的供体 DO11 T 细胞，以及继承 (a) 由不变链启动子或血管内皮启动子驱动的四环素反式激活因子和 (2) 膜-相关卵清蛋白融合蛋白，其表达受四环素反式激活因子调节。从野生型、lpr 或 gld DO11 小鼠获得的 T 细胞将被纳入分析中，因为在许多实验环境中发现 FasL 的过度表达会引发慢性纤维化反应。我们的结果应该为 SSc 的机制基础提供重要的见解，并为这种毁灭性疾病提供新的治疗策略。公众健康相关性：系统性硬化症 (SSc) 是一种具有显着发病率和死亡率的毁灭性疾病，目前尚无针对多种表现的有效治疗方法。这项研究可能有助于深入了解引发 SSc 发展的因素以及可能有助于限制患者疾病进展的策略。