Interleukin-21 as an Effective Suppressant for IgE-mediated Allergic Hypersensitivity Reactions

摘要

IgE plays essential roles in the pathogenesis of many allergic disorders including bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylaxis. If IgE production can be effectively and safely controlled in patients, such procedures may alleviate allergic symptoms, leading to novel therapeutic and prophylactic interventions of allergic diseases. Interleukin-21 (IL-21) is a cytokine produced by activated T cells. It exerts pleiotropic immunomodulatory functions through acting on various immune cells including T, B, and NK cells. To analyze influence of exogenous IL-21 in vivo, we inserted an expression unit of IL-21 cDNA into an Epstein-Barr virus (EBV)-based artificial chromosome, so that extremely powerful and long-lasting expression of the cytokine can be achieved in vivo in the liver. Peanut anaphylactic mice were established by repetitive immunization with the crude peanut extract (CPE) as an allergen, and they received intravenous administration of the DNA construct through the tail vein under high pressure. As the results, anaphylactic symptoms were completely abrogated by the IL-21 gene treatment, in striking contrast to untreated allergic mice that showed extremely severe systemic disturbance. Serum level of IgE was also drastically suppressed by IL-21 gene treatment. Then we used recombinant IL-21 (rIL-21) to treat anaphylactic as well as allergic rhinitis mice, which also showed significant remission of the diseases. As the mechanisms of the IgE regulation, we found that expression of germ line Cε transcript was suppressed in B cells that were treated with rIL-21 in vitro or in vivo, suggesting that IL-21 effectively suppressed the class switch recombination (CSR) to IgE. The present findings strongly suggest that IL-21 can be used as a novel molecular medicine to control allergy. It was also shown that the EBV-based artificial chromosome provides a useful means to analyze bioactivity in vivo of various genes in mammals, providing a platform to investigate functions of genes as well as to discover promising molecules for therapeutic molecular targeting to treat various disorders.