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Common Myeloid Progenitor-Derived IL-9 Regulates Gastrointestinal Mast Cell Density and Food Allergy Susceptibility

Award Number: R01AI195594
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/23/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Common Myeloid Progenitor-Derived IL-9 Regulates Gastrointestinal Mast Cell Density and Food Allergy Susceptibility - 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 in the increase in GI MC density in the predisposition and severity of food allergy19-23. Furthermore, our group unveiled an obligatory role for IL-9/IL-9R signaling in the regulation of intestinal MC expansion19,20,24. A current gap in knowledge is the cellular origin of IL-9 and the signals that stimulate induction of IL-9 and drive GI MC expansion and predisposition to food allergy. In preliminary studies, we have identified three IL-9eGFP+ cell populations within the GI tract of food allergic mice, FcRI+ common myeloid progenitor (CMP), innate lymphoid cell type 2 and CD4+ Th2 cells. Strikingly, we observed 1) that FcRI+ CMPs are the dominant source of IL-9 in the GI tract and levels correlated with food allergy severity and 2) the presence of CD34+ IL-9+ and CD4+ IL-9+ cells in duodenal biopsy samples from peanut allergic individuals. Collectively, these studies support the concept 1) that FcRI+ CMPs are the predominant source of IL-9 in food allergy and 2) the presence of GI tissue specific signals in the induction IL-9 in FcRI+ CMPs. We hypothesize that FcRI+ CMPs secrete IL-9 and regulate GI MC density and predisposition and severity of food allergy. To test our hypothesis, we propose three aims: To test our hypothesis, we propose three aims: 1) define the requirement of FcRI+ CMP-derived IL-9 in the expansion of GI MC density and Food Allergy; 2) determine the GI specific signals in the induction of IL-9 in FcRI+ CMPs and the role of IL-9+ FcRI+ CMPs in MC progenitor proliferation and maturation and 3) define human IL-9+ FcRI+ CMPs in Peanut allergy. With respect to the expected outcomes, Aim I will define a requirement for FcRI+ CMP-derived IL-9 in induction of GI MC expansion and predisposition of food allergy; 2) demonstrate a requirement of intestinal epithelial IL-33 signaling in the induction of IL-9 in FcRI+ CMPs and that this cell directly drive MC progenitor proliferation and maturation 3) establish FcεRI+ CMP-derived IL-9 as a central mediator in the pathogenesis of peanut allergy. 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $746,017 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	4/27/2026	NEW	$746,017
														Subtotal = $746,017

Grand Total All Awards = $746,017

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Common Myeloid Progenitor-Derived IL-9 Regulates Gastrointestinal Mast Cell Density and Food Allergy Susceptibility

Award Number: R01AI195594

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/23/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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