Immunological Basis of Anti-IgE Therapy

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DESCRIPTION:(Investigator's abstract): Recently, a therapy based on anti-IgE antibodies has been developed by pharmaceutical companies. The mechanism underlying the beneficial effect of this therapy is not completely understood, but is likely to be related to the marked reduction in the IgE level. Of note is the concomitant accumulation of IgE-anti-IgE complexes in the sera. Another remarkable effect of the treatment is the substantial reduction in the FcepsilonRI level on basophils. The existing literature suggests that the reduction in the IgE level is likely to result in a down-regulation of another IgE receptor, FcepsilonRII/CD23, which has an immunomodulatory function, suggesting that the therapy may result in other alterations of the immune system. We propose to conduct mechanistic studies of anti-IgE therapy in conjunction with a multicenter clinical trial designed to evaluate the efficacy of the therapy in preventing peanut-induced hypersensitivity. The specific aims of the proposed research are: I. Determination of the effect of anti-IgE therapy on FcepsilonRI expression and basophil responses. We will first confirm that anti-IgE therapy causes a reduction in the FcepsilonRI level on basophils and then analyze whether this occurs at a transcriptional level. We will confirm that the therapy causes a reduction in basophil response to cross-linkage of FcepsilonRI and then determine whether it also affects basophil response induced by non-IgE stimuli. The effect of the therapy on the FcepsilonRI level on skin mast cells will be investigated. 2. Determination of the effect of anti-IgE therapy on FcepsilonRII expression and antigen presentation. We will determine whether the therapy results in a down-regulation of FcepsilonRII/CD23 on B cells. Because of the demonstrated function of this receptor in antigen presentation, we will determine the antigen presentation by B cells from anti-IgE treated and control subjects. 3. Determination of the effect of anti-IgE therapy on antibody production. We will determine whether anti-IgE therapy results in a suppression of IgE production, in addition to sequestration of IgE. Whether IgE-anti-IgE complexes directly suppress IgE production by B cells in vitro will be investigated. The effect of the therapy on the IgG antibody response to allergen challenge will also be assessed. We hope that the knowledge obtained will improve our understanding of anti-IgE therapy and benefit future development of this therapy. We also hope that the studies will lead to a better understanding of the mechanisms of allergic diseases.