There is a fundamental gap in understanding how respiratory viral infections and atopy synergistically contribute to the development of acute exacerbations in individuals with allergic asthma. Plasmacytoid dendritic cells (pDCs) play a critical role in directing antiviral responses through the secretion of massive concentrations of Type I interferons (IFN). Impaired in vitro IFN responses to respiratory viruses have been demonstrated in pDCs isolated from individuals with allergic asthma. Moreover, in vitro pDC IFN responses to virus are inhibited by IgE-dependent mechanisms. As both IgE and expression of its receptor (Fc?RI) on pDCs are elevated in individuals with this disease, there is ample opportunity for IgE-mediated inhibition of pDC antiviral responses in patients with allergic asthma. The objective in this proposal is to investigate the effect of reducing IgE in vivo on pDC IFN responses in vitro using cells isolated from participants in an upcoming NIAID- sponsored randomized, placebo controlled clinical trial entitled Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE). The PROSE trial is designed to compare the efficacy of 3 treatments - omalizumab (an anti-IgE therapy), inhaled corticosteroid boost therapy, and placebo - in reducing fall exacerbations in patients with allergic asthma;it thus provides the optimal clinical setting to test the effect of reducing IgE on pDC IFN responses to viruses. The overlying hypothesis of this proposal is that reducing IgE concentrations in patients with allergic asthma will increase pDC IFN responses and reverse the inhibitory effects of allergen stimulation on pDC IFN responses. The rationale underlying this proposal is that since impaired pDC antiviral IFN responses in patients with allergic asthma are linked to IgE-mediated inhibitory pathways, there should be a role for decreasing IgE in enhancing pDC IFN responses. We will test our hypothesis by pursuing two specific aims: 1) Determine how omalizumab impacts pDC IFN responses. We will test this by comparing pDC IFN secretion and IFN-regulatory gene expression in participants before and after omalizumab therapy;and 2) Determine the impact of omalizumab on allergen and IgE cross-linking mediated inhibition of pDC IFN responses. We will test this by comparing the inhibitory effect of allergic stimulation on viral-induced pDC IFN secretion and IFN-regulatory gene expression in participants before and after treatment. The innovation of the approach resides in its focus on pDCs and their role in the apparent antagonism between IgE-mediated events and antiviral responses as well as the integration of these mechanistic studies into the upcoming clinical trial. The proposed research is significant because improved pDC IFN synthesis following omalizumab therapy could result in a decreased frequency of asthma exacerbations following respiratory viral infections. Ultimately, the new knowledge obtained will uncover mechanisms underlying the link between IgE-mediated pathways and viral-induced IFN signaling in pDCs and provide new insights into the prevention of viral-induced asthma exacerbations.
The proposed research is relevant to public health because the discovery of mechanisms underlying how allergens and respiratory viruses synergistically precipitate asthma exacerbations is ultimately expected to increase the understanding of the pathogenesis of allergic asthma and uncover targets for potential therapeutic strategies aimed at preventing exacerbations. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help enhance health and reduce the burden of illness associated with allergic asthma.
|Bajwa, Gagan; DeBerardinis, Ralph J; Shao, Baomei et al. (2016) Cutting Edge: Critical Role of Glycolysis in Human Plasmacytoid Dendritic Cell Antiviral Responses. J Immunol 196:2004-9|
|Teach, Stephen J; Gill, Michelle A; Togias, Alkis et al. (2015) Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol 136:1476-85|
|Huber, Jonathan P; Gonzales-van Horn, Sarah R; Roybal, Kole T et al. (2014) IFN-Î± suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells. J Immunol 192:5687-94|
|Pyle, David M; Yang, Victoria S; Gruchalla, Rebecca S et al. (2013) IgE cross-linking critically impairs human monocyte function by blocking phagocytosis. J Allergy Clin Immunol 131:491-500.e1-5|