The role of IL-12p40 in the response of pulmonary dendritic cells to tuberculosis

描述(申请人提供)：耐多药结核病(TB)的出现威胁到我们控制这种高度传染性和致命疾病的能力。美国国立卫生研究院已经认识到了这一威胁，PA-04-119的发布鼓励了有助于更好地了解结核病自然历史的研究。该应用程序通过研究肺对结核病的免疫反应的一个新方面来响应PA-04-119。具体地说，我们首次展示了细胞因子IL-12p40在结核分枝杆菌(Mtb)诱导的肺树突状细胞(DC)从肺向引流淋巴结(LN)迁移中的作用。我们还表明，在没有病原体诱导的迁移的情况下，几乎没有诱导抗原特异性的CD4T细胞反应，也完全失去了对疾病的免疫介导性保护。这一关于IL-12p40在结核病自然病程中的作用的新观察为研究IL-12p40介导其对肺树突状细胞的影响的机制提供了基础。通过了解这种细胞因子在微生物诱导的DC迁移中的作用，我们将不仅影响TB，还将影响通过肺部进入并受CD4T细胞介导的免疫反应控制的其他A、B或C类病原体。本研究的目的是研究Mtb在肺内诱导IL-12p40的途径，并确定IL-12p40介导Mtb诱导的DC迁移的机制。通过阐明IL-12p40对DC的作用机制，我们将深入了解Mtb如何调控免疫应答的诱导。在第一个目标中，我们将确定肺中哪些细胞需要产生IL-12p40以响应结核分枝杆菌，以便发生DC迁移。我们还将确定哪些受体是启动和传播DC迁移所必需的。在第二个目标中，我们将确定IL-12p40能够在多大程度上调节DC对趋化因子梯度的反应能力。我们将确定IL-12p40单独是否足以调节DC的迁移，或者微生物信号是否对这一过程至关重要。如果我们确定IL-12p40能够启动肺树突状细胞的迁移，那么在未来我们将检测IL-12p40刺激的DC在肺内启动细胞反应的能力。从长远来看，这可能为通过肺部途径输送疫苗的基于IL-12p40的佐剂提供基础。这项工作与公共卫生的相关性在于，它将增加我们对身体对细菌入侵的反应的理解。这种认识的增加将使我们能够采取有针对性的、新颖的干预措施，从而提高我们控制疾病的能力。

DESCRIPTION (provided by applicant): The emergence of multi-drug resistant tuberculosis (TB) threatens our ability to control this highly transmissible and deadly disease. The NIH has recognized this threat and research that will result in greater understanding of the natural history of TB has been encouraged by the release of PA-04-119. This application responds to PA-04-119 by investigating a novel aspect of the pulmonary immune response to TB. Specifically, we show for the first time data that demonstrate a role for the cytokine IL-12p40 in the Mycobacterium tuberculosis (Mtb)-induced migration of pulmonary dendritic cells (DC) from the lung to the draining lymph node (LN). We also show that in the absence of this pathogen-induced migration there is little to no induction of an antigen-specific CD4 T cell response and also a complete loss of immune-mediated protection against disease. This novel observation regarding the role of IL-12p40 in the natural history of TB provides a basis for investigation of the mechanisms whereby IL-12p40 mediates its effects on pulmonary DC. By understanding the role of this cytokine in microbially induced DC migration we will impact not only TB but also other class A, B or C pathogens that enter via the lung and are controlled by CD4 T cell-mediated immune responses. The objective of this proposal is to examine the pathway whereby Mtb induces IL-12p40 within the lung and determine the mechanism whereby IL-12p40 mediates the Mtb-induced migration of DC. By elucidating the mechanism of action of IL-12p40 on DC we will gain insight into how Mtb modulates the induction of the immune response. In Aim One we will determine which cells in the lung are required to produce IL-12p40 in response to Mtb in order for DC migration to occur. We will also determine which receptors are required to initiate and propagate the migration of DC. In Aim Two we will determine the extent to which IL-12p40 is capable of modulating the ability of DC to respond to a chemokine gradient. We will determine whether IL-12p40 alone is sufficient to mediate DC migration or whether a microbial signal is essential to this process. If we determine that IL-12p40 is capable of initiating migration of pulmonary DC then in the future we will examine the ability of IL-12p40 stimulated DC to initiate cellular responses within the lung. In the long term this could provide the basis for an IL-12p40 based adjuvant for vaccines delivered via the pulmonary route. The relevance of this work to public health is that it will increase our understanding of the response of the body to bacterial invasion. This increased understanding will allow targeted and novel interventions that will improve our ability to control disease.