Impact of Anti-IL-4 Therapy on Immune Polarization

描述（由申请人提供）：本提案的总体目标是研究全身抑制IL-4对人类免疫反应的影响。IL-4是一种主要的细胞因子，已被证明在免疫反应的极化中发挥关键作用，因此已成为操纵人体免疫反应的潜在重要靶点。为了确定治疗性抑制IL-4对人类的影响，我们将利用蛋白质设计实验室进行的II期试验的样本，在该试验中，单克隆抗IL-4将被施用于哮喘受试者。对照、低剂量和高剂量受试者将在治疗前第0天和药物效应预测峰值时间第90天采集样本。我们将确定抗il -4治疗对1)体内和体外肱骨免疫的影响，特别强调Ig同型产生的模式和2)免疫反应相关基因的表达谱。目的1将集中于确定抗il -4治疗对抗体反应的影响。这一目标将通过1A)确定抗il -4治疗对体内和体外诱导的IgM、IgG1、IgG4、IgA和IgE产生的影响，1B)比较IgH种系转录物的水平，1C)确定抗il -4对类开关重组到IgE的影响来实现。在Aim 2中，我们将确定抗il -4治疗对免疫相关基因表达谱的整体影响。这将通过利用基因微阵列（“芯片”）分析基因表达谱来完成。这些实验将确定与管家基因相比，一系列在免疫反应中具有明确作用和尚未确定作用的基因如何被抗il -4治疗改变。将比较Aim 2中基因表达谱与Aim 1中确定的免疫参数之间的关系，以确定基因表达谱与Ig产生之间的可能关系。总之，本实验将提供关于抗IL-4治疗对抗体反应和免疫反应的影响的直接信息，并暗示IL-4在人体体内的作用。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to investigate the impact of systemic inhibition of IL-4 on the profile of the immune response in humans. IL-4 is a master cytokine that has been shown to play a key role in polarization of immune responses and therefore has become a potential important target for manipulating the human immune response. To determine the effects of therapeutic inhibition of IL-4 in humans, we will make use of the samples from phase II trial being conducted by Protein Design Laboratories in which monoclonal anti-IL-4 will be administered to subjects with asthma. Samples will be obtained from control, low dose and high dose subjects at day 0 prior to treatment and at day 90, the predicted peak time of drug effect. We will determine the effects of anti-IL-4 therapy on 1) humeral immunity in vivo and in vitro with special emphasis on the pattern of Ig isotype production and 2) the expression profile of immune response related genes. Aim 1 will be focused on determining the impact of anti-IL-4 therapy on antibody responses. This aim will be accomplished by 1A) determining the effects of anti-IL-4 therapy on in vivo and in vitro induced IgM, IgG1, IgG4, IgA, and IgE production, 1B) comparing the levels of IgH germline transcripts and 1C) determining the effects of anti-IL-4 on class switch recombination to IgE. In Aim 2, we will determine the global effects of anti-IL-4 therapy on the expression profiles of immune related genes. This will be accomplished by analysis of the gene expression profiles utilizing the gene microarrays ("chips"). These experiments will determine how a whole array of genes with defined role and as yet to be defined roles in immune responses, in comparison with housekeeping genes, are altered by anti-IL-4 therapy. The relationship between the gene expression profiles in Aim 2 and the immune parameters determined in Aim 1 will be compared to determine possible relationships between the gene expression profiles and Ig production. Overall, the experiments in this proposal will provide direct information as to the impacts of anti-IL-4 therapy on antibody responses and immune responses and by implication, the role of IL-4 in vivo in humans.