Developmental Immunotherapeutics For Allergic Diseases A

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Abstract

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.