Impact of Anti-IL-4 Therapy on Immune Polarization

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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.