RECOMBINANT HUMAN INTERLEUKIN-4 RECEPTOR IN ASTHMA

点击翻译按钮获取中文摘要

DESCRIPTION (adapted from investigator's abstract): The enclosed application describes a series of studies to investigate the potential mechanisms of action of the recombinant human interleukin-4 receptor (rhuIL-4R) in asthma. These studies will be performed in association with a clinical trial of rhu-IL-4R in asthma sponsored by Immunex Corp. The applicants hypothesize that the administration of rhuIL-4R by nebulization produces clinical improvement in asthma, which is mediated through inhibition of Th2 lymphocytes in the lung. The clinical trail (Immunex protocol 13.0011) will evaluate the clinical efficacy of rhuIL-4R in a randomized, double blind, placebo-controlled phase II trial of 12 weekly nebulized doses of rhuIL-4R, 500 or 1500 micograms, in patients with mild and moderate allergic asthma. Evaluations will include the effects of IL-4R on spirometric measures, asthma symptoms, quality of life, and serum inflammation parameters in bronchoscopically obtained specimens taken before and after the clinical trial. The data from these subjects will be supplemented with data obtained from other patients subjected to segmental allergen challenge with or without treatment with rhuIL-4R. Interleukin (IL)-4 is essential both for the differentiation of Th2-like lymphocytes and for the inhibition of apoptosis of established Th2 cells. Neutralization of IL-4 within the asthmatic airway should therefore lead to rapid disappearance of identifiable Th2-like cells and their associated cytokines. The applicant will attempt to confirm the hypothesis that rhuIL-4R inhibits Th2-like cellular differentiation and function by assessing whether such treatment inhibits production of the Th2-associated cytokines IL-3, IL-4, IL-5, IL-9, and GM-CSF. These studies will also assess whether rhuIL-4R will induce apoptosis, as demonstrated as fragmentation of DNA, enhanced production of IL-10, up-regulated expression of CTLA4 and Fas (CD95), and down-regulation of Bcl-2. Decreased biological activity of IL-4 may also be manifested as reduced expression of VCAM-1 on bronchial epithelial tissue and decreased release of CD23 from B lymphocytes and monocytes into BAL fluid. If the treatment results in decreased production of IL-5 and other eosinophil-activating cytokines, this in turn should result in diminished expression of VCAM-1 and reduced eosinophil recruitment into the airway. Finally, we propose to correlate clinical responsiveness to rhuIL-4R with specific polymorphisms involved in interleukin-4 signaling, including IL-4, IL-4 receptor, stat-6, and bcl-6 genes. We hypothesize that individuals who are genetically predisposed to either increased IL-4 production or IL-4 responsiveness will represent a cohort more likely to benefit from the IL-4 antagonists.