Immune correlates of reactivation tuberculosis

描述（由申请人提供）：在人类中，结核病与IL-10产生增加高度相关，并且使用鼠模型已证实IL-10在疾病进展中的关键作用。在这项研究中，我们建议使用体外和体内技术研究IL-10如何影响疾病进展。我们将利用CBA/J小鼠品系，其与人相似，在感染M的过程中可以在体内天然产生丰富的IL-10。结核使用CBA/J小鼠品系作为我们的主要模型，我们将通过研究在这种细胞因子存在下改变的免疫功能来确定IL-10产生增加导致疾病进展的机制。除了研究产生大量IL-10的菌株中感染的自然进展外，我们还将施用抗IL-10 R抗体以确切地确定IL-10如何对疾病进展产生生物学影响。此外，我们将研究是否阻断IL-10的作用可以逆转这种特定的小鼠品系的易感性表型，这一事件将具有特别相关的治疗和预防结核病在man. This建议的目标是使用CBA/J小鼠品系作为一种工具，以确定在体内的作用和相关性的IL-10感染M。结核这是最好的实现使用小鼠模型，其中丰富的IL-10的生产已与疾病进展。对IL-10如何促进疾病进展的更基本的理解将提供有关导致个体易患活动性结核病的因素的关键信息。此外，对IL-10介导疾病进展的机制的理解将有助于开发可能延迟甚至预防结核病的治疗性治疗。

DESCRIPTION (provided by applicant): In man, tuberculosis disease is highly associated with increased IL-10 production and the use of murine models has confirmed a critical role for IL-10 in disease progression. In this grant we propose to investigate how IL-10 can influence disease progression using both in vitro and in vivo techniques. We will take advantage of the CBA/J mouse strain which, in similarity to man, can naturally produce abundant IL-10 in vivo during infection with M. tuberculosis. Using the CBA/J mouse strain as our primary model we will determine the mechanism by which increased IL-10 production leads to disease progression by investigating the immune functions that are altered in the presence of this cytokine. In addition to investigating the natural progression of infection in a strain that produces abundant IL-10 we will also administer anti-IL-10R antibodies to determine exactly how IL-10 has a biological influence on disease progression. Furthermore, we will investigate whether blocking the action of IL-10 can reverse the susceptibility phenotype of this particular mouse strain, an event that would have particular relevance to the treatment and prevention of tuberculosis disease in man. The goal of this proposal is to use the CBA/J mouse strain as a tool to determine the in vivo role and relevance of IL-10 during infection with M. tuberculosis. This is best achieved using a mouse model in which abundant IL-10 production has been linked with disease progression. A more fundamental understanding of how IL-10 facilitates disease progression will provide critical information about the factors that contribute to an individual's susceptibility to develop active tuberculosis. Additionally, an understanding of the mechanism(s) by which IL-10 mediates disease progression would aid in the development of therapeutic treatments that may delay or even prevent tuberculosis disease.