NOVEL MHC CLASS II CONSTRUCTS FOR TREATMENTS OF CBD

描述：慢性铍病(CBD)是一种类似于肺部的疾病 临床表现为其他肉芽肿性疾病，如结节病、分裂肌病等 和肺结核。大约有80万人面临着罹患 这种疾病是由金属和相对不溶的化合物引起的 铍。这种疾病最初是一种致敏细胞介导的免疫反应， 铍抗原，发展成非干酪性肉芽肿。证据 强烈提示CD4+T细胞和MHC类2等位基因HALDPB1*0201是 在CBD的免疫发病机制中具有重要作用。T细胞受体(TCR)是如何 T细胞与铍和MHC相互作用的机制是 CBD的发病机制尚不清楚。批判性地检验这一假设 一种特定的MHC 2类等位基因与铍相互作用并诱导T细胞 提出了直接参与CBD发病机制的反应。 开发一系列新型的重组人类白细胞抗原-DP结构，将 选择性地消除铍对炎性T细胞的反应。这将是 能够测试这种T细胞反应在CBD中的作用。发展和 对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，进而， T细胞免疫反应和谱系。这些分子可以提供模板 用于设计一种治疗CBD的新方法。PI建议：1)表征 重组人白细胞抗原-DP的生化构筑，2)结合特性 铍与重组人类白细胞抗原-DP构建物的相互作用，3)鉴定 高效力的BE/抗原组合可导致肿瘤细胞的增殖 致病T细胞和4)确定耐受的最佳条件 铍特有的人类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.