Spontaneous Autoimmune Model of Peripheral Neuropathy

周围神经病变的自发性自身免疫模型

• 批准号: 8116742
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116742
• 关键词: Address; Animals; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune thyroiditis; Autoimmunity; Axon; CD28 gene; CD80 gene; Cells; Characteristics; Complex; Critical Pathways; Development; Diabetes Mellitus; Disease; Exocrine pancreas; Fluorescence; Genetic; Goals; Grant; Hybridomas; Image; Immunotherapy; In Vitro; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Japanese Population; Knowledge; Lead; Lesion; Link; Modeling; Molecular; Mouse Protein; Mouse Strains; Mus; Neuropathy; Non obese; Organ; Pathogenicity; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Polyneuropathy; Predisposition; Production; Proteins; Reagent; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Reporter; Research Personnel; Role; Schwann Cells; Sialadenitis; Signal Transduction; Specificity; Study models; System; T-Cell Receptor; T-Lymphocyte; Testing; Thyroiditis; Tissues; Transgenic Mice; Transgenic Organisms; autoreactive T cell; base; cytokine; cytotoxicity; immunopathology; in vivo; islet; mouse model; novel; peptide A; promoter; relating to nervous system; tool

DESCRIPTION (provided by applicant): The treatment and cure of autoimmunity remains of paramount importance. The challenges to developing successful therapies are broad, ranging from complex genetics, similarities and differences among target tissues, differential pathogenic mechanisms and an incomplete knowledge of the target antigens. We have shown that the Non-Obese Diabetes (NOD) mouse strain can be used as a mouse model of multiple autoimmune disorders (AID). These other autoimmune diseases were most apparent when regulatory T cells (Tregs) were eliminated and co-stimulatory pathways altered. For instance, NOD mice develop a spontaneous autoimmune disease of the peripheral nervous system, termed Spontaneous Autoimmune Peripheral Polyneuropathy (SAPP), in the absence of CD28 interaction with B7-2. In addition, we observed that in the complete absence of CD28 signals, NOD mice were deficient in Tregs and developed SAPP, sialadenitis, autoimmune thyroiditis and a newly appreciated autoimmune exocrine disease similar to that observed in "fulminant type 1 diabetes" described in Japanese and some Australian patients. Significantly, these various autoimmune diseases could use different pathogenic and co-stimulatory pathways and result from the recognition of distinct as well as potentially overlapping self-antigen specificities. These results have led to the conclusion that the NOD mouse represents a unique model for studying multi-organ autoimmunity. The combination of genetic propensity for autoimmunity and the tools that we have developed in this mouse strain will be exploited to address several key questions. Do unique and/or overlapping antigen specificities distinguish/link these diseases? Are the pathogenic pathways evident for one disease critical for the manifestation of others? Are there common co-stimulation pathways that control the susceptibility and progression of these distinct autoimmune diseases? The following aims are proposed to address these questions: Specific Aim #1: To generate tissue antigen-specific effector and regulatory T cell TCR Tg mice based on candidate antigens. Specific Aim #2: To generate tissue antigen-specific effector and regulatory T cell TCR Tg mice using T cell hybridomas and mimotopes. Specific Aim #3: To determine the effector and regulatory pathways and the role of co-stimulation in the distinct autoimmune diseases in NOD mice. Specific Aim #4: To develop green fluorescence protein (GFP)-specific systems to study autoimmunity in NOD mice. Together, the results of these studies will test the hypothesis that the phenotypic manifestation of multi- organ autoimmune diseases is regulated by a coalescence of common and tissue-specific pathways. Moreover these common and distinct pathways are critical for understanding of the immunopathology of these different autoimmune diseases and development of novel therapies.

描述（由申请人提供）：自身免疫的治疗和治愈仍然至关重要。开发成功疗法的挑战是广泛的，范围从目标组织之间的复杂遗传学，相似性和差异，差异性致病机制以及对靶抗原的不完整知识。我们已经表明，非肥胖糖尿病（NOD）小鼠菌株可用作多种自身免疫性疾病（AID）的小鼠模型。当消除调节性T细胞（Treg）并改变共刺激途径时，这些其他自身免疫性疾病最为明显。例如，在没有CD28与B7-2相互作用的情况下，点头小鼠会形成周围神经系统的自发自身免疫性疾病，称为自发性自身免疫性周围性多神经病（SAPP）。此外，我们观察到，在完全没有CD28信号的情况下，NOD小鼠在Tregs缺乏，发育不良，sialadenitis，腹部炎，自身免疫性甲状腺炎以及新近欣赏的自身免疫性外分泌疾病，类似于“ 1型型糖尿病”中的自身免疫性疾病。值得注意的是，这些各种自身免疫性疾病可以使用不同的致病性和共刺激途径，并源于对不同和潜在重叠自我抗原特异性的识别而导致的。这些结果得出的结论是，点头小鼠代表了研究多器官自身免疫性的独特模型。自身免疫性的遗传倾向与我们在这种小鼠菌株中开发的工具的结合将被利用以解决几个关键问题。独特和/或重叠的抗原特异性是否区分/联系这些疾病？对于一种对另一种疾病至关重要的一种疾病，致病途径是否显而易见？是否有控制这些独特的自身免疫性疾病的易感性和进展的常见共刺激途径？提出了以下目的来解决以下问题：具体目的＃1：基于候选抗原产生组织抗原特异性效应子和调节性T细胞TCR TG小鼠。特定目的＃2：使用T细胞杂交瘤和模型生成组织抗原特异性效应子和调节性T细胞TCR TG小鼠。特定目的3：确定效应子和调节途径以及共刺激在NOD小鼠不同自身免疫性疾病中的作用。特定目的＃4：开发绿色荧光蛋白（GFP）特异性系统来研究NOD小鼠的自身免疫性。总之，这些研究的结果将检验以下假设：多器官自身免疫性疾病的表型表现受共同和组织特异性途径的合并调节。此外，这些常见和不同的途径对于理解这些不同自身免疫性疾病的免疫病理学和新型疗法的发展至关重要。