IMMUNE RESPONSE MODIFYING VACCINES FOR ASTHMA

改变哮喘免疫反应的疫苗

• 批准号: 2901893
• 负责人: Shoshana Levy
• 金额: $ 26.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2901893
• 关键词: T lymphocyte; asthma; chimeric proteins; cholera toxin; cytokine; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; immunoconjugates; immunomodulators; immunotherapy; laboratory mouse; leukocyte activation /transformation; ovalbumin; tissue /cell culture; vaccine development; vector vaccine

The long-term goals of this project are to develop novel immune response-modifying vaccines for the treatment of asthma. Asthma is a major public health problem, and affects 15 million Americans, roughly 5-8 percent of the population. It has increased substantially in prevalence and in terms of mortality and morbidity over the past two decades, and this increase has occurred despite a substantial improvement in our understanding of asthma pathophysiology and the availability of improved medications for asthma. We propose to generate therapeutic fusion proteins and constructs for asthma by molecularly linking a prototypic allergen, ovalbumin (OVA), to an immune response polarizing cytokine, IL-18, and to a tolerogenic agent, cholera toxin, subunit B. We will use these immunotherapeutic agents in a murine model for asthma, and convert established, pathogenic Th2-dominated, allergic inflammatory responses into protective responses. The proposed studies are based on our previous results, which demonstrated that allergen immunotherapy improves allergic disease by correcting the underlying immune dysregulation, and that the efficacy of immunotherapy can be greatly improved by the use of antigen-cytokine fusion constructs. These constructs, by directing the activity of potent cytokines and other agents towards antigen-specific T cells, rectify the cytokine profile and activity of such pathogenic allergen-specific Th2 cells. Here we propose to produce and study more potent allergen-fusion proteins as well as cDNA plasmid vaccines containing OVA and IL-18 in established models of allergic inflammation and airway hyperreactivity. In addition, we will determine the role of allergen specific Th1 cells, other regulatory T cells (Th3, CD8, or gammadelta T cells), and of peripheral tolerance in down regulating allergic inflammation and asthma. These innovative studies will provide the basis for development of new disease-modifying strategies to treat and potentially cure patients with allergy and asthma. In addition, these studies will expand our understanding of the role of T cells that protect against these common disorders.

该项目的长期目标是开发用于治疗哮喘的新型免疫反应修饰疫苗。 哮喘是一个主要的公共卫生问题，影响着 1500 万美国人，约占总人口的 5-8%。 在过去的二十年中，尽管我们对哮喘病理生理学的了解以及改进的哮喘药物的可用性有了很大的提高，但在过去的二十年中，其患病率以及死亡率和发病率均大幅增加。我们建议通过分子连接原型过敏原卵清蛋白 (OVA) 与免疫反应极化细胞因子 IL-18 和致耐受剂霍乱毒素 B 亚基来生成治疗性融合蛋白和构建体来治疗哮喘。我们将使用这些在小鼠哮喘模型中使用免疫治疗剂，并将已建立的、致病性 Th2 主导的过敏性炎症反应转化为保护性反应。 拟议的研究基于我们之前的结果，该结果表明过敏原免疫疗法通过纠正潜在的免疫失调来改善过敏性疾病，并且通过使用抗原-细胞因子融合构建体可以大大提高免疫疗法的疗效。 这些构建体通过将强效细胞因子和其他试剂的活性导向抗原特异性 T 细胞，纠正此类致病性过敏原特异性 Th2 细胞的细胞因子谱和活性。在这里，我们建议在已建立的过敏性炎症和气道高反应性模型中生产和研究更有效的过敏原融合蛋白以及含有 OVA 和 IL-18 的 cDNA 质粒疫苗。 此外，我们将确定过敏原特异性 Th1 细胞、其他调节性 T 细胞（Th3、CD8 或 gammadelta T 细胞）以及外周耐受在下调过敏性炎症和哮喘中的作用。 这些创新研究将为开发新的疾病缓解策略提供基础，以治疗和潜在治愈过敏和哮喘患者。 此外，这些研究将扩大我们对 T 细胞预防这些常见疾病的作用的理解。