IL-9-producing MC precursor ancestry and function in Food Allergy

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Food allergy has increased at an alarming rate from 2005-2014 in the US, with a disproportionally higher incidence in children2-5. Clinical symptoms of food allergy (FA) range from mild reactions to severe, potentially lethal anaphylaxis6 and there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option15. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of effective and safe therapies8. Over the last 15 years, our team has made several seminal contributions that unveiled a critical role for IL-9/IL-9R-axis and gastrointestinal (GI) mast cells (MC) load in the eliciting of IgE-mediated food allergy. Consistent with this, we have identified a hypogranular, IL-9 producing MC precursor (MCp9) population that is sufficient for induction of food allergy symptoms in different mice strains. The current gap in knowledge is the cellular origin and cytokine sequelae that underlie the development and function of MCp9s and that the presence of this cell in humans. In preliminary studies we have made several transformative observations: 1) that MCp9s are derived from the bipotential basophil / MC progenitor (FcRI- MCp) and not the committed MC progenitor (FcRI+ MCp), 2) sequence stimulation with TGF and IL-33 is required for the development of MCp9; 3) TGF1 priming for MCp9 formation is associated with SMAD2/3 activation and TGFR1-dependent and 3) IL-33-induction of Il9 expression is NFkB-dependent. Finally, we have developed a iPS-cell derived human hematopoietic culture system and identified human MCp9 cells (CD117+ FcRI+ 7high CD203c- IL-9+) cells and revealed the presence of Tryptase+ IL-9+ cells in duodenal biopsy samples from food allergic individuals. We hypothesize that MCp9 cells are derived from a MC precursor population, induced by sequence-dependent TGFIL-33 signaling axis and regulates GI MC density in food allergy models. To test our hypothesis, we propose three aims: 1) Define MCp9 ancestry in mice and humans; 2) Define the requirement of Il9 CNS25 enhancer element in MCp9 fate determination and function and 3) Define the contribution of MCp9 cells to GI MC tissue density in food Allergy. With respect to the expected outcomes, the studies proposed in Aim I are expected to define murine and human MCp9 ancestry and functionality; 2) Define the involvement of sequential TGF and IL-33 signals in the regulation of the Il9 CNS25 element in MCp9 formation and 3) demonstrate a requirement for MCp9-derived IL- 9 in Food Allergy and define the relationship of this cell with peanut allergy and oral immunotherapy outcomes. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms underpinning GI MC density in food allergy and the requirement of this cell in increased MC tissue density in food allergy, thereby directing the development of new and pre-existing therapeutics for treating food allergy and anaphylaxis.