Alterations in Innate Immune Function of FcERI-Bearing Cells during Manipulations

Johns Hopkins University, Baltimore MD

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Abstract

Since its discovery some forty years ago, immunoglobulin (lg)E antibody is perhaps the most central[unreadable] factor known contributing to the pathogenesis of allergic inflammation and disease. Whereas its role in[unreadable] triggering histamine and leukotriene C4 (LTC4) release from basophils and mast cells has long been[unreadable] appreciated, the nature of this immunoglobulin in modulating the function of other IgE receptor-bearing[unreadable] cells is poorly understood. In particular, this immunoglobulin is also known to bind and modulate the[unreadable] function of dendritic cells (DC), which are the most potent antigen-presenting cells (APCs) known to[unreadable] initiate immune responses by activating naive T cells for effector functions. Our preliminary in vitro data[unreadable] has recently identified novel phenotypic and functional changes in DC upon cross-linking IgE on the[unreadable] surface of these cells. Specifically, these data imply a mechanism were allergen, by cross-linking[unreadable] IgE/receptor complexes, counter-regulates specific innate immune responses in DC that are normally[unreadable] pro-Th1 (i.e. anti-allergic) in nature. Thus, IgE may very well augment the maturation of DC into APC[unreadable] that promote allergic disease by preventing cytokine responses in these cells that normally prevent[unreadable] progression of allergic inflammation. By depleting IgE in vivo using omalizumab administration, the Aims[unreadable] presented in this project should provide "proof-of-concept" that IgE does, indeed, play a critical role in[unreadable] regulating innate and adaptive immune capabilities of DC and consequently the activity of other immune[unreadable] cells dependent of and/or regulated by DC function. In Aim 1. we will monitor the loss of IgE receptor[unreadable] expression on DC from Cat and Food allergic subjects receiving omalizumab and investigate these cells[unreadable] for changes in specific innate and adoptive immune responses ex vivo. In Aim 2. phenotypic and[unreadable] functional markers related to innate and adaptive immunity will also be monitored in/on human basophils[unreadable] following omalizumab administration. We hypothesis that relevant cytokines (IL-4 and IL-13) prominently[unreadable] secreted by these cells in response to allergen, but also in response to specific innate immune stimuli,[unreadable] will additionally be inhibited with IgE depletion. Finally, we have shown that allergen exposure induces[unreadable] systemic "priming" effects in blood basophils, which inversely relate to DC innate immune responses. In[unreadable] Aim 3. we'll explore the effect of depleting IgE using omalizumab to better define the role of this[unreadable] immunoglobulin in these clinically relevant responses, including those occurring in the lung. Overall,[unreadable] these studies should resolve mystery surrounding the role IgE plays in suppressing innate immune[unreadable] responses, and provide new insights into the pathophysiology and treatment of allergic disease states.