Food allergy has become a major health problem in westernized countries and now affects 3.5% - 4% of the U.S. population with cow's milk allergy [CMA] affecting 2.5% of young children. CMA provides an ideal model to study immunologic mechanisms responsible for allergic disease and tolerance induction. It is a common food allergic disorder that reflects both the "transient" form of food allergy that is "outgrown," as seen in many other childhood food allergies [e.g. egg, soy, wheat], and the "persistent," more severe form, similar to life-long peanut, tree nut and seafood allergies. Diagnosis is definitive with the blinded food challenge, the responsible allergens [milk proteins] are well characterized including their 3-dimensional structures, and good animal models have been established that enable dissection of immunologic and systemic mechanisms at the molecular level. Over the past granting period, we demonstrated that the majority of children with IgE-mediated CMA can safely ingest baked [heat-denatured] milk products without adverse effects and identified a variety of immunologic markers [humoral and cellular] that distinguish them from the minority of children with persistent CMA who cannot tolerate any form of milk protein. Using animal models and epithelial cell lines, it was shown that IgE and CD23 are required for enhanced allergen uptake in the small intestine and are found in the stool of food-allergic but not non-allergic children, supporting their role in the allergic diathesis as well as their potential for use as a biomarker of clinical food allergy. Studies in a murine model of CMA also showed that the way specific milk proteins traffick in the Gl mucosa may play a critical role in the ultimate response of the host;i.e. immunologic tolerance vs. allergen sensitization and clinical tolerance vs. allergic reaction. Based on knowledge acquired in our previous Center grant, we will further explore clinical and underlying immunologic responses in one clinical trial examining the effects of graded exposure to heat-denatured milk products, and in a second clinical trial of milk oral immunotherapy [OIT] plus omalizumab, which we hypothesize will induce "tolerance," as opposed to "desensitization" seen with standard milk OIT. We also will use novel models to delineate properties that make certain milk proteins allergenic, explore how they are processed at the cellular level, and define the role of facilitated CD23 transport in food allergic disease. Through the unique resources and collaborative projects outlined in this Center application, successful completion of the aims may lead to new paradigms in the management and treatment of food allergies and provide novel biomarkers for the diagnosis and management of patients. PROJECT 1: Immunologic Responses to Cow's Milk Proteins in IgE-mediated Cow's Milk Allergy (Sampson, H) PROJECT 1 DESCRIPTION (provided by applicant): Cow's milk is the most common cause of food allergy in children, with approximately 1.8% of American infants developing IgE-mediated allergic reactions to cow's milk [~74,000 cases/year]. While ~80% "outgrow" their milk allergy by the 6th birthday, 35% will develop other food allergies and about 60% develop respiratory allergy and asthma. Milk allergy provides an ideal "experiment of nature" to study immunologic mechanisms associated with oral tolerance induction to food and allergic disease. It is the most common food allergy in American children and reflects both the "transient" form of food allergy that is "outgrown," similar to many other childhood food allergies [e.g. egg, soy, wheat], and the "persistent," more severe form, similar to peanut, nuts and seafood allergies. It can be definitively diagnosed with the blinded food challenge and the responsible allergens, milk proteins, are well characterized, including their 3-dimensional structures. Although strict milk avoidance diets have been the "standard of care" for milk-allergic patients, our recent data suggest that the majority of children will tolerate heat-denatured products without deleterious effects. In addition, preliminary studies with oral immunotherapy [OIT] have reported effective "desensitization" of milk-allergic patients, but whether true "tolerance" can be induced with this therapy remains to be demonstrated.
In Aim #1 of this project, we will delineate clinical phenotypes of milk-allergic patients based upon their response to various forms of heat-denatured milk proteins, identify novel biomarkers differentiating the subgroups, and elucidate immunologic changes that accompany acquisition of tolerance. Furthermore, we hypothesize that progression toward immunological tolerance will occur more rapidly in children who are actively ingesting milk protein, and that tolerance will be associated with distinct changes in humoral and cellular function.
In Aim #2 we will determine whether the combination of anti-lgE and milk OIT will induce clinical "tolerance" compared to the "desensitization" seen with OIT alone, and monitor associated immunologic changes. In conjunction with the other projects in this Center application, successful completion of these Aims will provide new insight into the immunologic changes associated with the development of oral tolerance to food, delineate phenotypic and immunologic differences in milk-allergic individuals, and possibly lead to a new paradigm in the medical management and treatment of milk-allergic individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI044236-14
Application #
8234037
Study Section
Special Emphasis Panel (ZAI1-QV-I (J1))
Program Officer
Minnicozzi, Michael
Project Start
2000-08-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$1,577,203
Indirect Cost
$767,165
Name
Icahn School of Medicine at Mount Sinai
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Savilahti, Emma M; Kuitunen, Mikael; Valori, Miko et al. (2014) Use of IgE and IgG4 epitope binding to predict the outcome of oral immunotherapy in cow's milk allergy. Pediatr Allergy Immunol 25:227-35
Jarvinen, K M; Westfall, J E; Seppo, M S et al. (2014) Role of maternal elimination diets and human milk IgA in the development of cow's milk allergy in the infants. Clin Exp Allergy 44:69-78
Caubet, Jean-Christoph; Nowak-Wegrzyn, Anna; Moshier, Erin et al. (2013) Utility of casein-specific IgE levels in predicting reactivity to baked milk. J Allergy Clin Immunol 131:222-4.e1-4
Blazquez, Ana Belen; Knight, Adina Kay; Getachew, Hoheteberhan et al. (2010) A functional role for CCR6 on proallergic T cells in the gastrointestinal tract. Gastroenterology 138:275-84.e1-4
Savilahti, Emma M; Rantanen, Ville; Lin, Jing S et al. (2010) Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes. J Allergy Clin Immunol 125:1315-1321.e9
Shreffler, Wayne G; Wanich, Niya; Moloney, Marla et al. (2009) Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein. J Allergy Clin Immunol 123:43-52.e7
Skripak, Justin M; Sampson, Hugh A (2008) Towards a cure for food allergy. Curr Opin Immunol 20:690-6