Tuberculosis Immunity in Young Children

描述（由申请人提供）：结核病（TB）是全球感染性发病率和死亡率的最重要原因之一。幼儿更有可能感染结核分枝杆菌（Mtb），并因其病原体而患上严重疾病。这些临床观察结果可能反映了幼儿和成人免疫系统的根本差异。与结核病免疫相关的关键差异包括婴儿和幼儿对免疫原产生TH2型CD4+ T细胞的倾向，对病原体产生TH1型T细胞的缺陷，以及巨噬细胞和树突状细胞（DC）功能的缺陷。我们建议系统地定义，在幼儿（小于或等于10岁），这些重要的差异相关的成功遏制结核分枝杆菌感染。具体目标是：1）确定幼儿Mtb感染后疾病的严重程度是否与TH 2型Mtb特异性免疫相关，反之，Mtb感染后疾病的消失是否与TH 1型Mtb特异性免疫相关。2)确定免疫不成熟是否与结核分枝杆菌感染后TH 2型结核分枝杆菌特异性免疫的发展相关，反之，免疫成熟是否与结核分枝杆菌感染后TH 1型结核分枝杆菌特异性免疫的发展相关。3)通过表征来自健康新生儿的脐带血的巨噬细胞和DC的表型和功能，与健康成人中的巨噬细胞和DC功能进行比较，评价与Mtb感染相关的先天免疫方面。这些研究可能有助于更全面地了解幼儿的结核病免疫力，从而促进为这一脆弱人群开发改进的结核病疫苗。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Young children are more likely to contract infection with and develop severe disease from the causative agent Mycobacterium tuberculosis (Mtb). These clinical observations likely reflect fundamental differences in the immune systems of young children and adults. Critical differences relevant to TB immunity include the propensity for infants and young children to develop TH2-type CD4+ T cells in response to immunogens, deficiencies in the development of TH1-type T cells in response to pathogens, and deficiencies in macrophage and dendritic cell (DC) function. We propose to systematically define, in young children (less than or equal to 10 years of age), these important differences relevant to the successful containment of Mtb infection. The specific aims are: 1) To determine if severity of disease following Mtb infection in young children is associated with TH2-type Mtb-specific immunity, and conversely, if absence of disease following Mtb infection is associated with TH 1-type Mtb-specific immunity. 2) To determine if immunologic immaturity is associated with the development of TH2-type Mtb-specific immunity following Mtb infection, and conversely if immunologic maturity is associated with the development of TH 1-type Mtb-specific immunity following Mtb infection. 3) To evaluate aspects of innate immunity relevant to Mtb infection by characterizing the phenotype and function of macrophages and DC from cord blood derived from healthy neonates in comparison to macrophage and DC function in healthy adults. These studies may contribute to a more complete understanding of TB immunity in young children, and hence 'facilitate the development of an improved TB vaccine for this vulnerable population.