RECOMBINANT HUMAN INTERLEUKIN-4 RECEPTOR IN ASTHMA

描述（改编自研究者摘要）：随附申请 描述了一系列研究，以调查潜在的作用机制 重组人白细胞介素-4受体（rhuIL-4 R）在哮喘中的作用。这些 研究将与rhu-IL-4 R的临床试验联合进行， 申请人假设， 通过雾化给予rhuIL-4 R产生临床改善， 哮喘，其通过抑制肺中的Th 2淋巴细胞介导。 临床试验（Immunex方案13.0011）将评价临床 rhuIL-4 R在随机、双盲、安慰剂对照II期研究中的疗效 12周一次的rhuIL-4 R雾化剂量试验，500或1500微克， 轻、中度过敏性哮喘患者。评价将包括： IL-4 R对肺量测定、哮喘症状、生活质量的影响， 在支气管镜下采集的样本中的血清炎症参数 在临床试验之前和之后这些受试者的数据将 补充了从其他患者获得的数据， 用或不用rhuIL-4 R处理的过敏原攻击。白细胞介素-4 对于Th 2样淋巴细胞的分化和细胞增殖都是必需的。 抑制已建立的Th 2细胞的凋亡。内中和IL-4 因此哮喘气道应导致 可识别的Th 2样细胞及其相关细胞因子。申请人将 试图证实rhuIL-4 R抑制Th 2样细胞的假说， 通过评估这种治疗是否抑制了 Th 2相关细胞因子IL-3、IL-4、IL-5、IL-9和GM-CSF的产生。 这些研究还将评估rhuIL-4 R是否会诱导细胞凋亡， 表现为DNA断裂，IL-10的产生增加， CTLA 4和Fas（CD 95）表达上调，Bcl-2表达下调。 IL-4的生物活性降低也可以表现为降低的 VCAM-1在支气管上皮组织上的表达和 CD 23从B淋巴细胞和单核细胞进入BAL液。如果治疗结果 在IL-5和其他嗜酸性粒细胞活化细胞因子的产生减少中， 反过来应导致VCAM-1表达减少和嗜酸性粒细胞减少 呼吸道中的募集。最后，我们建议将临床 对rhuIL-4 R的反应性，特异性多态性涉及 白细胞介素-4信号传导，包括IL-4、IL-4受体、stat-6和bcl-6 基因.我们假设那些有遗传倾向的人 增加的IL-4产生或IL-4反应性将代表一个群组 更有可能从IL-4拮抗剂中获益。

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.