MOLECULAR STUDIES OF ANTIGENS THAT CAUSE LUNG DISEASE

在世界范围内，对过敏原产生的过敏性 屋尘螨是最重要的风险因素， 哮喘的发展。超过10种不同的螨过敏原已经被 通过基因克隆技术鉴定。这项建议的目的是 以确定第2组过敏原的分子结构， 开发与IgE反应性降低的过敏原变体 抗体的Der p 2的三级结构将由下式确定： 核磁共振光谱（NMR）和X射线 结晶学Der p2变体将由研究中心指导生成 将评估这些变体的诱变和反应性 通过立即皮肤试验，血清IgE抗体反应和T细胞 应答 显示出降低的皮肤试验反应性的变体，但是 保留T细胞表位，将被选择用于I期研究 免疫疗法在螨过敏患者中的应用。IgE抗体和T细胞 对尘螨1、2、5和7类过敏原的反应将 进行比较，以确定其相对过敏的重要性， 选择重组过敏原的混合物用于诊断， 治疗目的。 由第二种螨类产生的过敏原， 热带假单胞菌，这是一个重要的原因，哮喘在 热带，将被克隆，它们的过敏关系将被 研究了这些研究最初将侧重于第5组 过敏原和多中心皮肤试验研究将在 几个国际中心比较生物活性， Blo t 5和Der p 5。 这将使适合 待评价的用于诊断的重组过敏原， 对Blomia和Dermatophagoides spp.比较 不同的地理区域。 这些研究的预期结果 最重要的是， 将确定重要螨过敏原，重组体 将产生用于过敏诊断和治疗的蛋白质， 比天然过敏原提取物副作用少， 研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.