NOVEL MHC CLASS II CONSTRUCTS FOR TREATMENTS OF CBD

描述：慢性呼吸道疾病（CBD）是一种类似于 临床上与其他肉芽肿性疾病如结节病、子宫肌瘤 和肺结核。大约有80万人面临发展中国家的风险。 这种疾病是由金属和相对不溶性的化合物引起的， 铍。该疾病开始于致敏细胞介导的免疫反应， 铍抗原会发展成非干酪化性肉芽肿证据 强烈表明CD 4 + T细胞和MHC 2类等位基因HALDPB 1 *0201是 在CBD的免疫发病机制中很重要。T细胞受体（TCR）是如何 T细胞与铍和MHC相互作用， CBD的发病机制尚不清楚。为了严格检验这个假设 一个特定的MHC 2等位基因与铍相互作用，诱导T细胞 反应，直接有助于CBD的发病机制，建议 开发一个新的重组HLA-DP构建体家族， 选择性消除炎症T细胞对铍的反应。这将 能够测试这种T细胞反应在CBD中的作用。发展和 这些新结构的表征将提供机会， 确定控制T细胞的独特干预点， T细胞免疫反应和库。这些分子可以提供模板 设计一种新的CBD治疗方法PI建议：1）描述 重组HLA-DP构建体的生物化学，2）表征结合 铍与重组HLA-DP构建体的相互作用，3）鉴定 高效力BE/抗原组合负责 致病性T细胞和4）确定耐受化的最佳条件 铍特异性人类T细胞

DESCRIPTION: Chronic Beryllium Disease (CBD) is a lung disease similar clinically to other granulomatous diseases such as sarcoidosis, schizomyosis and tuberculosis. Approximately 800,000 individuals are at risk for developing the disease, which is caused by metal and relatively insoluble compounds of beryllium. The disease begins as a sensitizing cell mediated immune response to beryllium antigen, which develops into a non-caseating granuloma. Evidence strongly suggests that CD4 plus T-cells and MHC class 2 allele HALDPB1*0201 are important in the immunopathogenesis of CBD. How the T-cell receptor (TCR) on the T-cells interacts with beryllium and the MHC and the mechanism that gives rises to the pathogenesis of CBD is unknown. To test critically the hypothesis that a specific MHC class 2 allele interacts with beryllium and induces T-cell responses that contribute directly to the pathogenesis of CBD, it is proposed to develop a family of novel recombinant HLA-DP constructs that will selectively eliminate inflammatory T-cell responses to beryllium. This will enable the testing of the role of such T-cell responses in CBD. Development and characterization of these novel constructs will provide the opportunity to identify unique points of intervention for controlling T-cells and in turn, the T-cell immune response and repertoire. These molecules may provide a template for engineering a novel treatment of CBD. The PI proposes to: 1) Characterize the recombinant HLA-DP constructs biochemically, 2) Characterize the binding interaction of beryllium with the recombinant HLA-DP constructs, 3) Identify high potency BE/antigen combinations responsible for proliferation of pathogenic T-cells and 4) To determine optimal conditions for tolerizing beryllium specific human T-cells.