Spontaneous Autoimmune Model of Peripheral Neuropathy

描述（由申请人提供）：自身免疫的治疗和治愈仍然是至关重要的。开发成功疗法的挑战是广泛的，包括复杂的遗传学、靶组织之间的相似性和差异性、不同的致病机制和对靶抗原的不完整了解。我们已经证明，非肥胖型糖尿病（NOD）小鼠品系可用作多种自身免疫性疾病（AID）的小鼠模型。当调节性T细胞（Tcells）被消除并且共刺激途径改变时，这些其他自身免疫性疾病最明显。例如，NOD小鼠在不存在CD 28与B7-2相互作用的情况下发生外周神经系统的自发性自身免疫性疾病，称为自发性自身免疫性外周多发性神经病（SAPP）。此外，我们观察到，在完全缺乏CD 28信号，NOD小鼠TdR缺乏，并发展SAPP，涎腺炎，自身免疫性甲状腺炎和一个新认识的自身免疫性外分泌疾病类似于在日本和一些澳大利亚患者中描述的“暴发性1型糖尿病”中观察到的。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和共刺激途径，并且由识别不同的以及潜在重叠的自身抗原特异性引起。这些结果导致的结论是，NOD小鼠代表了一个独特的模型，用于研究多器官自身免疫。将利用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的组合来解决几个关键问题。独特的和/或重叠的抗原特异性区分/联系这些疾病？一种疾病的致病途径对其他疾病的表现是否至关重要？是否有共同的共刺激途径控制这些不同的自身免疫性疾病的易感性和进展？具体目标#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。具体目的#2：使用T细胞杂交瘤和模拟表位产生组织抗原特异性效应子和调节性T细胞TCR Tg小鼠。具体目标#3：确定NOD小鼠中不同自身免疫性疾病中的效应子和调节途径以及共刺激的作用。具体目标#4：开发绿色荧光蛋白（GFP）特异性系统，以研究NOD小鼠的自身免疫。总之，这些研究的结果将检验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联合调节的假设。此外，这些共同和不同的途径是至关重要的理解这些不同的自身免疫性疾病的免疫病理学和新的治疗方法的发展。

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.