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，小鼠模型的使用证实了IL-10在疾病进展中的关键作用。在这项拨款中，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小鼠菌株，它与人相似，在感染结核分枝杆菌时可以在体内自然产生大量的IL-10。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的菌株感染的自然进展外，我们还将使用抗il - 10r抗体来确定IL-10如何对疾病进展产生生物学影响。此外，我们将研究阻断IL-10的作用是否可以逆转这种特定小鼠品系的易感性表型，这一事件将与人类结核病的治疗和预防特别相关。本研究的目的是利用CBA/J小鼠菌株作为工具，确定IL-10在结核分枝杆菌感染过程中的体内作用和相关性。这最好是通过小鼠模型来实现的，在小鼠模型中，大量的IL-10产生与疾病进展有关。对IL-10如何促进疾病进展的更基本的了解将提供有关导致个体易感性发展为活动性结核病的因素的关键信息。此外，了解IL-10介导疾病进展的机制将有助于开发可能延缓甚至预防结核病的治疗方法。

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.