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区别包括婴儿和幼儿对免疫原反应产生TH2型CD4+T细胞的倾向，以及对病原体反应产生TH1型T细胞的缺陷。此外，世界上儿童结核病患病率较高的地区也存在寄生虫病和艾滋病的沉重负担，这可能会增加形成TH2型免疫的倾向，并侵蚀TH1型免疫。 在乌干达，艾滋病毒和寄生虫感染在儿童中很常见，我们建议在乌干达的幼儿(~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。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无病与TH1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生有关，反之，免疫成熟度是否与结核分枝杆菌感染后TH1-1型结核分枝杆菌特异性免疫的发生有关。3)探讨HIV混合感染对结核病患儿T细胞免疫功能的影响。这些研究可能有助于更全面地了解幼儿的结核病免疫情况，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 and deficiencies in the development of TH1-type T cells in response to pathogens. Furthermore, parts of the world with a high prevalence of childhood TB also have heavy burdens of parasitic disease and AIDS, which may increase the propensity to develop TH2-type immunity and erodes TH1-type immunity, respectively. We propose to systematically define, in young children (~ 10 years old) from Uganda, where HIV and parasitic infections are common in children, 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 TH1-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 TH1-1ype Mtb-specific immunity following Mtb infection. 3) To determine if HIV co-infection affects the development of T cell immunity in children with tuberculosis. 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.