Understanding the Persistence of Immune-mediated Chronic Diseases

描述（由申请人提供） 摘要：自身免疫和哮喘是免疫介导的疾病，可以持续一个人的一生，造成经济，身体，心理和社会负担。许多这些疾病的特点是症状期或耀斑，其次是一段时间的缓解。许多因素，如压力和感染，被认为是造成这种模式的原因。在这些疾病中，T细胞持续受到自身或环境抗原的刺激。与自身免疫性疾病一样，暴露于病原体（导致慢性感染）也会导致持久性抗原对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，在最初的感染爆发已经解决之后。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学情况有关，因此在本提案中要检验的假设是，在已建立的疾病期间，在自身免疫和哮喘中，特异于组织和环境抗原的T细胞的产生是否是导致组织损伤永久化的因素。这一假设将在不同的糖尿病模型、多发性硬化症模型和一种新的哮喘模型中进行检验。此外，在这些慢性疾病以及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以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，这些研究可能为某些免疫性疾病的慢性化提供新的解释，并为治疗干预提供新的范例。 公共卫生相关性：本文提出的研究旨在了解随着时间的推移产生的新T细胞如何导致自身免疫性疾病和哮喘症状的爆发。这也可以帮助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细胞可能会导致统一的治疗，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.