Exocrine Gland Targeting in Autoimmune NOD Mice

自身免疫 NOD 小鼠的外分泌腺靶向

• 批准号: 6777036
• 负责人: AMMON B PECK
• 金额: $ 25.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777036
• 关键词: B lymphocyte; NOD mouse; Sjogren' s syndrome; autoimmunity; cell death; cytokine; disease /disorder model; exocrine glands; gene targeting; genetically modified animals; humoral immunity; immunoregulation; lacrimal apparatus; pathologic process; salivary glands

DESCRIPTION (provided by applicant): Sjogren's syndrome, one of the connective tissue autoimmune diseases, presents clinically as a loss of exocrine secretory function due to autoaggression primarily against the salivary and lacrimal glands. The mechanism(s) underlying the tissue specific destruction of target organs in Sjogren's syndrome is not understood at the present time. Our studies have now established the NOD (non-obese diabetic) and NOD.B10.H2b mice as the best animal models for secondary and primary Sjogren's syndrome, respectively. To date, the NOD mouse remains the only animal identified to develop the corresponding pathophysiology of salivary gland secretion loss and lacrimal tear production in conjunction with the histological observation of lymphocytic infiltration of the exocrine tissues. Results of our studies have novel implications in how we define the autoimmune disease paradigm with the observation of exocrine gland cellular alterations which develop in the absence of a functional lymphocyte system (NOD-scid). Autoimmune diseases, such as IDDM, IBD, and Hashimoto's thyroiditis, similar to our studies in both the NOD-scid and NOD parental strain, indicate nonimmune factors, as a consequence of genetically programmed loss of glandular differentiated function or homeostasis, appear to contribute to initiating the disease process. Using a second congenic strain lacking B-cells (NOD.Igu null), the loss of secretory function was shown to be independent of T-cells but not autoantibodies. To elucidate further the mechanism(s) responsible for the loss of exocrine target tissue function of Sjogren' s syndrome-like disease in the NOD model, the following specific aims are proposed: 1. Define the role of regulatory effector cytokines modulating the humoral response in autoimmune exocrinopathy through the analysis of specific knockout mice; and 2. Define the components of the humoral immune response promoting exocrine gland destruction, using the NOD mouse models of Sjogren's syndrome. These studies will expand on our novel observations which established the NOD mouse as an appropriate model for the study of Sjogren's syndrome-like pathology by analyzing the role of the humoral immune system components and effector cytokines in the precipitation of exocrine tissue dysfunction. By using a global approach to the analyses of this autoimmune disease involving a coordinated evaluation of both the lacrimal and salivary glands, the results from this research will provide innovative insights into the mechanism(s) triggering autoimmune attack on specific tissues and further suggest novel strategies for the control of this tissue destruction.

描述(申请人提供)：干燥综合征，一种结缔组织病 组织自身免疫性疾病，临床表现为外分泌功能丧失 主要针对唾液和泪腺的自身攻击所致的功能 腺体。靶组织特异性破坏的机制(S) 干燥综合征的器官目前尚不清楚。我们的研究 现在已经建立了NOD(非肥胖糖尿病)和NOD.B10.2b小鼠作为 继发性干燥综合征和原发性干燥综合征的最佳动物模型。 到目前为止，NOD鼠仍然是唯一被发现具有 唾液腺分泌丧失与泪液分泌异常的相应病理生理机制 泪液产生与淋巴细胞的组织学观察 外分泌组织的渗出。我们的研究成果具有新颖性 对我们如何定义自身免疫性疾病范例的影响 缺血时外分泌腺细胞变化的观察 功能性淋巴细胞系统(NOD-SCID)。自身免疫性疾病，如 IDDM、IBD和桥本甲状腺炎，与我们在 因此，NOD-SCID和NOD亲本菌株表明是非免疫因素 遗传性程序性腺体分化功能丧失或 动态平衡，似乎有助于启动疾病过程。使用 缺乏B细胞的第二个同源菌株(NOD.Igu缺失)，分泌功能丧失 功能被证明是独立于T细胞，而不是自身抗体。至 进一步阐明外分泌靶点丢失的机制(S) 干燥S综合征样疾病NOD模型的组织功能 提出了以下具体目标：1.明确监管效应者的角色 细胞因子通过调节自身免疫性外分泌病的体液反应 对特定基因敲除小鼠的分析；以及2.定义 体液免疫反应促进外分泌腺破坏，使用点头 干燥综合征小鼠模型。这些研究将对我们的小说进行扩展 为NOD小鼠建立一个合适的模型的观察 从体液的作用看干燥综合征的病理 沉淀中的免疫系统成分和效应细胞因子 外分泌组织功能障碍。通过使用全球方法对此进行分析 自身免疫性疾病涉及泪液和泪液的协调评估 唾液腺，这项研究的结果将提供创新 对特定组织触发自身免疫攻击的机制的洞察(S) 并进一步提出了控制这种组织的新策略 毁灭。