Developmental Immunotherapeutics For Allergic Diseases A

本项目旨在开发过敏性疾病的新型免疫疗法，以及了解其作用机制和合理应用所需的实验室技术。我们已经完成了一项临床试验，研究了omalizumab/抗IgE治疗对嗜碱性粒细胞和抗原提呈细胞上高亲和力IgE受体（FcepsilonRI）表达的影响。在最初的临床研究中（Lin等），对为期6周的试验进行了详细的动力学分析，比较了对过敏原攻击的临床反应与血清IgE和嗜碱性粒细胞FcepsilonRI下调的免疫学终点。虽然血清IgE在治疗后3天最大限度地降低，但最大的临床反应需要2-4周，与下调嗜碱性粒细胞FceRI表达所需的时间相似。该报告首次提供了关于omalizumab起效的详细临床和免疫学数据。FcepsilonRI下调的相似动力学和临床反应表明，FcepsilonRI下调可能是抗ige治疗起作用的重要机制。

This project seeks to develop novel immunologic therapies for allergic diseases as well as the laboratory techniques required to understand their mechanisms of action and rational application. We have completed a clinical trial examining the effects of omalizumab/anti-IgE therapy on expression of the high affinity IgE receptor (FcepsilonRI) on basophils and antigen presenting cells. In the primary clinical study (Lin et al), a detailed kinetics analysis over a 6-week trial compared the clinical response to allergen challenge to the immunological endpoints of serum IgE and down regulation of basophil FcepsilonRI. Although serum IgE was maximally decreased by 3 days after treatment, maximum clinical responses took 2-4 weeks, similar to the time required for down regulation of basophil FceRI expression. This report provides the first detailed clinical and immunological data on omalizumab onset of action. The similar kinetics of FcepsilonRI down regulation and the clinical response suggest that FcepsilonRI down regulation may be an important mechanism through which anti-IgE therapy works. In a second publication (Prussin et al) resulting from this clinical study we examined the effect of omalizumab therapy on FcepsilonRI expression by dendritic cells. We have previously reported that the two major subsets of human dendritic cells, termed DC1 and DC2 cells, express FcepsilonRI and that this expression is correlated to serum IgE concentration. In the current project, we further examined the relationship of DC expression of FcepsilonRI to IgE by dropping serum IgE concentration using omalizumab. During the above clinical trial of omalizumab we serially examined FcepsilonRI expression in DC1 and DC2 cells. Omalizumab caused a significant drop in both DC1 and DC2 expression of FcepsilonRI, whereas there was no significant change in the placebo group. Omalizumab decreased FcepsilonRI expression by 52% and 83% for DC1 and DC2 cells, respectively. Furthermore, the decrease in FcepsilonRI expression was highly correlated with the drop in serum IgE, suggesting a direct relationship between the two variables. These results further support our previous conclusions that serum IgE is a major factor driving FcepsilonRI expression by DCs. These data support the concept that novel therapeutic approaches directly targeted at FcepsilonRI expression would affect both the sensitization and effector phases of the allergen specific immune response.