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