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(申请人提供)：自身免疫的治疗和治愈仍然是最重要的。开发成功的治疗方法面临的挑战是广泛的，包括复杂的遗传学、靶组织之间的相似和不同、不同的致病机制以及对靶抗原的不完全了解。我们已经证明，非肥胖糖尿病(NOD)小鼠品系可以用作多发性自身免疫性疾病(AID)的小鼠模型。当调节性T细胞(Tregs)被消除，共刺激途径改变时，这些其他自身免疫性疾病最为明显。例如，NOD小鼠在缺乏CD28与B7-2相互作用的情况下，会患上一种自发性周围神经系统自身免疫性疾病，称为自发性自身免疫性多发性神经病(SAP)。此外，我们观察到，在完全缺乏CD28信号的情况下，NOD小鼠缺乏Treg，并出现SAP、涎腺炎、自身免疫性甲状腺炎和一种新认识的自身免疫性外分泌疾病，类似于日本和一些澳大利亚患者所描述的暴发型1型糖尿病。值得注意的是，这些不同的自身免疫性疾病可能使用不同的致病和共刺激途径，并由于识别不同的和可能重叠的自身抗原特异性而导致。这些结果得出结论，NOD小鼠代表了研究多器官自身免疫的独特模型。结合自身免疫的遗传倾向和我们在这种小鼠品系中开发的工具，将被用来解决几个关键问题。独特的和/或重叠的抗原特异性是否区分/联系这些疾病？一种疾病的致病途径是否对其他疾病的表现至关重要？是否有共同的共刺激途径来控制这些不同的自身免疫性疾病的易感性和进展？提出了以下目标来解决这些问题：具体目标#1：基于候选抗原建立组织抗原特异性效应和调节性T细胞TCRTg小鼠。特定目的#2：利用T细胞杂交瘤和模拟表位建立组织抗原特异性效应和调节性T细胞TCRTG小鼠。具体目标#3：确定效应和调节途径以及共刺激在NOD小鼠不同的自身免疫性疾病中的作用。具体目的#4：建立绿色荧光蛋白(GFP)特异性系统来研究NOD小鼠的自身免疫。总而言之，这些研究的结果将检验这样一个假设，即多器官自身免疫性疾病的表型表现受到共同和组织特异性途径的共同调控。此外，这些共同和独特的途径对于了解这些不同自身免疫性疾病的免疫病理机制和开发新的治疗方法至关重要。