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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070345-04
Application #
7901045
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$270,296
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Sterba, Patricia M; Hamilton, Robert G; Saini, Sarbjit S (2015) Suppression of basophil Fc?RI activation by serum from active chronic idiopathic/spontaneous urticaria (CIU/CSU) subjects. J Invest Dermatol 135:1454-1456
Narisety, Satya D; Frischmeyer-Guerrerio, Pamela A; Keet, Corinne A et al. (2015) A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol 135:1275-82.e1-6
Gorelik, Mark; Narisety, Satya D; Guerrerio, Anthony L et al. (2015) Suppression of the immunologic response to peanut during immunotherapy is often transient. J Allergy Clin Immunol 135:1283-92
McGowan, Emily C; Savage, Jessica H; Courneya, Jean-Paul et al. (2014) Relationship of IgE to basophil phenotypes in peanut-sensitized adults. J Allergy Clin Immunol 134:746-749.e6
Macglashan Jr, Donald W; Saini, Sarbjit S (2013) Omalizumab increases the intrinsic sensitivity of human basophils to IgE-mediated stimulation. J Allergy Clin Immunol 132:906-11.e1-4
Saini, Sarbjit S; MacGlashan Jr, Donald W (2012) Assessing basophil functional measures during monoclonal anti-IgE therapy. J Immunol Methods 383:60-4
MacGlashan Jr, D (2012) Subthreshold desensitization of human basophils re-capitulates the loss of Syk and Fc?RI expression characterized by other methods of desensitization. Clin Exp Allergy 42:1060-70
MacGlashan Jr, Donald W (2012) IgE-dependent signaling as a therapeutic target for allergies. Trends Pharmacol Sci 33:502-9
Savage, Jessica H; Courneya, Jean-Paul; Sterba, Patricia M et al. (2012) Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy. J Allergy Clin Immunol 130:1123-1129.e2

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