Tuberculosis Immunity in Young Children

描述(申请人提供)：结核病(TB)是导致全球传染病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(结核分枝杆菌)引起的严重疾病。这些临床观察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反应的TH2型CD4+T细胞的倾向，对病原体反应的TH1型T细胞的发育不足，以及巨噬细胞和树突状细胞(DC)功能的缺陷。我们建议在幼儿(小于或等于10岁)中系统地界定这些与成功控制结核分枝杆菌感染有关的重要差异。其具体目的是：1)确定幼儿感染结核分枝杆菌后的疾病严重程度是否与TH2型结核分枝杆菌特异性免疫有关，反之，是否结核分枝杆菌感染后的疾病消失与1型结核分枝杆菌特异性免疫有关。2)确定免疫不成熟是否与结核分枝杆菌感染后TH2型结核分枝杆菌特异性免疫的发展有关，反之，免疫成熟是否与结核分枝杆菌感染后TH1型结核分枝杆菌特异性免疫的发展有关。3)通过对健康新生儿脐带血来源的巨噬细胞和DC的表型和功能进行分析，并与健康成人的巨噬细胞和DC功能进行比较，以评估与结核分支杆菌感染有关的先天免疫。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.