MOLECULAR STUDIES OF ANTIGENS THAT CAUSE LUNG DISEASE

在世界范围内，对过敏原产生的过敏性致敏作用 由屋尘粉尘是最重要的危险因素 哮喘的发展。已经有超过10种不同的螨类过敏原 通过基因克隆技术进行鉴定。这项提议的目的是 确定第2组变应原的分子结构和 开发与IgE反应性降低的过敏原变异体 抗体。Der p 2的三级结构将由 核磁共振波谱和X射线 结晶学。DER p 2变种将由站点定向生成 将评估这些变种的诱变性和反应性。 通过即刻皮肤试验，血清IgE抗体反应和T细胞 回应。显示皮肤测试反应性降低的变种，但 保留T细胞表位，将被选择用于I期研究 对尘螨过敏患者的免疫治疗的影响。IgE抗体与T细胞 对第1、2、5和7组变应原的反应将 进行比较以确定它们的相对过敏性重要性 筛选重组变应原鸡尾酒用于诊断和治疗 治疗目的。第二种螨类产生的过敏原， 热带布洛米亚，这是引起哮喘的一个重要原因 将被克隆，它们的致敏关系将被 调查过了。这些研究最初将重点放在第五组 过敏原和多中心皮肤测试研究将在 几个国际中心比较其生物活性 BLO t 5和Der p 5。这将使 用于诊断的重组变应原有待评估和 对Blomia和粉尘螨致敏。被比较于 不同的地理区域。这些研究的预期结果 是大多数的结构和生物学意义 重要的尘螨变应原将被确定，而重组 将产生用于过敏诊断和治疗的蛋白质， 具有天然过敏原提取的较少副作用，用于 开发更好的哮喘免疫疗法。

On a worldwide basis, allergic sensitization to allergens produced by house dust mites is the most important risk factor for the development of asthma. Over 10 different mite allergens have been identified by gene cloning techniques. The aims of this proposal are to determine the molecular structure of the Group 2 allergens and to develop allergen variants that have reduced reactivity with IgE antibodies. The tertiary structure of Der p 2 will be determined by nuclear magnetic resonance spectroscopy (NMR) and by X-ray crystallography. Der p 2 variants will be generated by site directed mutagenesis and the reactivity of these variants will be assessed by immediate skin tests, serum IgE antibody responses and T cell responses. Variants which show reduced skin test reactivity, but retain T cell epitopes, will be selected for use in a Phase I study of immunotherapy in mite allergic patients. IgE antibody and T cell responses to Dermatophagoides Group 1, 2, 5, and 7 allergens will be compared to determine their relative allergenic importance and to select cocktails of recombinant allergens for diagnostic and therapeutic purposes. Allergens produced by a second mite species, Blomia tropicalis, which is an important cause of asthma in the tropics, will be cloned and their allergenic relationships will be investigated. These studies will initially focus on the Group 5 allergens and a multi-center skin test study will be carried out at several international centers to compare the biologic activity of Blo t 5 and Der p 5. This will enable the suitability of recombinant allergens for diagnosis to be evaluated and sensitization to Blomia and Dermatophagoides spp. to be compared in different geographic areas. The expected outcome of these studies is that the structure and biologic significance of the most important mite allergens will be determined, and that recombinant proteins will be produced for allergy diagnosis and treatment, which have fewer side effects that natural allergen extracts, for use in developing better immunotherapies for asthma.