Developmental Immunotherapeutics For Allergic Diseases A

该项目旨在开发用于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，检查奥马珠单抗/抗IgE治疗对嗜碱性粒细胞和抗原呈递细胞上高亲和力IgE受体（FcepsilonRI）表达的影响。在主要临床研究（Lin et al）中，一项为期6周的试验的详细动力学分析比较了过敏原激发的临床应答与血清IgE和嗜碱性粒细胞FcepsilonRI下调的免疫学终点。尽管血清IgE在治疗后3天最大程度降低，但最大临床应答需要2-4周，与嗜碱性粒细胞FceRI表达下调所需的时间相似。本报告首次提供了奥马珠单抗起效的详细临床和免疫学数据。FcepsilonRI下调和临床应答的相似动力学表明，FcepsilonRI下调可能是抗IgE治疗发挥作用的重要机制。 在该临床研究的第二篇出版物（Prussin et al）中，我们检查了奥马珠单抗治疗对树突状细胞表达FcepsilonRI的影响。我们以前曾报道，两个主要的人类树突状细胞亚群，称为DC 1和DC 2细胞，表达FcepsilonRI，这种表达与血清IgE浓度相关。在本项目中，我们通过使用奥马珠单抗降低血清IgE浓度，进一步检查了Fc ε RI的DC表达与IgE的关系。在奥马珠单抗的上述临床试验期间，我们连续检测了DC 1和DC 2细胞中的Fc ε RI表达。奥马珠单抗导致Fc cepsilonRI的DC 1和DC 2表达显著下降，而安慰剂组无显著变化。奥马珠单抗分别使DC 1和DC 2细胞的FcepsilonRI表达降低了52%和83%。此外，FcepsilonRI表达的降低与血清IgE的降低高度相关，表明两个变量之间存在直接关系。这些结果进一步支持了我们先前的结论，即血清IgE是驱动DC表达Fc ε RI的主要因素。这些数据支持直接靶向Fc ε RI表达的新型治疗方法将影响过敏原特异性免疫应答的致敏和效应阶段的概念。

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.