Understanding the Persistence of Immune-mediated Chronic Diseases

描述(由申请人提供) 摘要：自身免疫和哮喘是一种免疫介导性疾病，可持续一生，造成经济、身体、心理和社会负担。其中许多疾病的特点是出现症状期或症状发作，然后是缓解期。压力和感染等多种因素被认为是造成这种模式的原因。在这些疾病中，T细胞受到自身或环境抗原的持续刺激。与自身免疫性疾病一样，接触病原体会导致慢性感染，也会导致持续性抗原对T细胞的持续刺激。我最近证明，新的病原体特异性T细胞在感染的慢性阶段不断产生，在最初的感染暴发消退之后很久。这种持续的胸腺输出是维持免疫反应所必需的。由于共同的特征可能与不同的免疫状况有关，本建议中要检验的假设是，在已确定的疾病期间，自身免疫和哮喘中针对组织和环境抗原的T细胞的产生是否是导致组织损伤永久化的一个因素。这一假设将在糖尿病、多发性硬化症和一种新的哮喘模型中进行测试。此外，在这些慢性疾病期间以及在慢性感染期间，对胸腺输出的操纵将决定新开发的T细胞是否可以被编程来抑制特应性或自身免疫性疾病或增强抗微生物免疫。如果成功，这些研究可能会为某些免疫疾病的慢性化提供一种新的解释，并提供一种治疗干预的新范式。 与公共卫生的相关性：这里提出的研究旨在了解随着时间的推移产生的新的T细胞如何有助于自身免疫性疾病和哮喘症状的发作。这也可能有助于我们理解为什么这些疾病会持续一生。通过药物或切除胸腺来操纵新产生的T细胞，可能会导致一种统一的治疗方法，以干扰多种疾病和慢性感染。

DESCRIPTION (Provided by the applicant) Abstract: Autoimmunity and asthma are immune-mediated diseases, which can last for the lifetime of an individual, causing financial, physical, psychological and societal burdens. Many of these diseases are characterized by symptomatic periods or flares, followed by a time of remission. Multiple factors, such as stress and infections, are believed to be responsible for this pattern. During these diseases, T cells are persistently stimulated by self or environmental antigens. Like autoimmune diseases, exposure to pathogens, which cause a chronic infection, also results in constant T cell stimulation by persistent antigens. I have recently demonstrated that new, pathogen-specific T cells are constantly produced during the chronic phase of infection, well after the initial infectious burst has resolved. This continued thymic output was required for maintaining the immune response. As common features can pertain to different immunological situations, the hypothesis to be tested in this proposal is whether the generation of T cells specific for tissue and environmental antigens in autoimmunity and asthma during established disease is a factor responsible for perpetuation of tissue damage. This hypothesis will be tested in different models of diabetes, multiple sclerosis and a novel model of asthma. In addition, manipulation of thymic output during these chronic diseases, as well as during chronic infections, will determine whether newly developed T cells can be programmed to dampen atopic or autoimmune diseases or augment anti-microbial immunity. If successful, these studies may offer a novel explanation for the chronicity of certain immunological diseases and provide a new paradigm on which to base therapeutic intervention. Public Health Relevance: The research proposed here aims to understand how new T cells that are produced over time contribute to flares in symptoms of autoimmune diseases and asthma. This may also help us to understand why these diseases last a lifetime. Manipulation of newly produced T cells through drugs or removal of the thymus may result in a uniform treatment to interfere with multiple diseases and chronic infections.