DEVELOPMENTAL IMMUNOTHERAPEUTICS FOR ALLERGIC DISEASES AND ASTHMA

该项目旨在开发治疗过敏性疾病的新的免疫疗法，以及了解其作用机制和合理应用所需的实验室技术。我们开发了一种高度敏感的过敏原特异性T细胞细胞因子分析方法，使我们能够直接高通量地检测临床试验中的细胞因子反应。正在采取的策略包括给予sIL-4受体作为哮喘的抗炎/Th2耐受疗法。我们正在将类似的方法应用于小鼠疫苗模型，以了解DNA疫苗是如何产生特异性免疫反应的。到目前为止，我们已经检查了细胞因子对空气变应原的反应，显示在过敏性哮喘患者中有统一的Th2反应，但在健康对照组中几乎没有检测到反应。因此，T细胞对空气变应原的正常反应是耐受。这表明，治疗性诱导对过敏原的耐受可能是治疗过敏性哮喘的一种有吸引力的策略。一项拟议的使用重组人白介素12作为过敏原免疫治疗佐剂的I期试验最近因监管原因而终止。抗原特异性细胞因子流已被应用于小鼠的DNA免疫，表明DNA疫苗在CD4阳性和CD8阳性的亚群中都产生了持久的Th1极化免疫反应，而蛋白质免疫产生的反应更多地局限于CD4阳性T细胞。-哮喘、过敏、T细胞、耐受性、治疗、疫苗、Th2细胞、白介素4、血液、免疫调节-人类受试者

This project seeks to develop novel immunologic therapies for allergic diseases as well as the laboratory techniques required to understand their mechanism of action and rational application. We have developed a highly sensitive allergen specific T cell cytokine assay, which allows us a direct high throughput means to examine cytokine responses in clinical trials. Strategies that are being pursued include the administration of sIL-4 receptor as an anti-inflammatory/Th2 tolerogenic therapy for asthma. We are applying a similar approach to mouse vaccine models to understand how DNA vaccines generate specific immune responses.To date, we have examined the cytokine response to aeroallergens, demonstrating a uniform Th2 response in allergic asthmatics but little or no detectable response in healthy controls. Thus, the normal T cell response to aeroallergens is tolerance. This suggests that the therapeutic induction of tolerance to allergens may be an attractive strategy for the treatment of allergic asthma. A proposed phase I trial using rhIL-12 as an adjuvant in allergen immunotherapy was recently terminated for regulatory reasons. Antigen specific cytokine flow has been applied to DNA vaccination of mice, demonstrating that DNA vaccination creates a long lasting Th1 polarized immune response in both CD4-positive and CD8-positive subsets, whereas protein immunization generates a more transient response limited to CD4-positive T cells. - Asthma, allergy, T cells, tolerance, therapy, vaccine, Th2 cells, interleukin-4, blood, immunomodulation - Human Subjects