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）：自身免疫性疾病的治疗和治愈仍然至关重要。开发成功疗法面临的挑战是广泛的，包括复杂的遗传学、靶组织之间的相似性和差异、不同的致病机制以及对靶抗原的不完整了解。我们已经证明，非肥胖糖尿病（NOD）小鼠品系可以用作多种自身免疫性疾病（AID）的小鼠模型。当调节性 T 细胞 (Treg) 被消除且共刺激通路发生改变时，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，NOD 小鼠会出现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周围多发性神经病 (SAPP)。此外，我们观察到，在完全缺乏 CD28 信号的情况下，NOD 小鼠缺乏 Tregs，并出现 SAPP、唾液腺炎、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，类似于日本和日本描述的“暴发性 1 型糖尿病”中观察到的疾病。一些澳大利亚患者。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，并且是由于对不同以及可能重叠的自身抗原特异性的识别而产生的。这些结果得出这样的结论：NOD 小鼠代表了研究多器官自身免疫的独特模型。自身免疫的遗传倾向与我们在该小鼠品系中开发的工具的结合将被用来解决几个关键问题。独特和/或重叠的抗原特异性是否区分/关联这些疾病？一种疾病的明显致病途径是否对其他疾病的表现至关重要？是否存在共同的共刺激途径来控制这些不同自身免疫性疾病的易感性和进展？提出以下目标来解决这些问题： 具体目标#1：基于候选抗原产生组织抗原特异性效应器和调节性 T 细胞 TCR Tg 小鼠。具体目标#2：使用 T 细胞杂交瘤和模拟表位生成组织抗原特异性效应器和调节性 T 细胞 TCR Tg 小鼠。具体目标#3：确定效应器和调节途径以及共刺激在 NOD 小鼠中不同自身免疫性疾病中的作用。具体目标#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。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是由常见和组织特异性途径的联合调节的。此外，这些共同和独特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开发新疗法至关重要。