Cow milk allergy [CMA] affects 2.5% of infants in the first 2 years of life or about 100,000 new cases per year in the U.S. IgE-mediated mechanisms account for 60% of these milk allergic disorders, with the majority involving the skin, while the majority of non-IgE-mediated reactions involve the gastrointestinal tract. About 80% of infants """"""""outgrow"""""""" their CMA [develop clinical tolerance] in the first 3 - 4 years of life, but 35% of children with IgE-mediated CMA develop other food allergies and 60% develop respiratory allergy. Over the past granting period, we have enrolled a large cohort of well-defined patients with CMAs, compared humoral and cellular responses in different patient groups, and identified unique allergenic epitope recognition in patients with persistent CMA. However, the underlying milk-induced immunopathology of these disorders and their subsequent resolution remain poorly understood. Utilizing primary intestinal epithelial cell lines from different patient groups with CMA and normal controls, no differences were found in antigen processing including trafficking, cathepsin expression and activity, antigenic peptides, or the capacity to stimulate CD4 + or CD8 + T cell proliferation. Murine models of IgE-mediated CMA and isolated gut loops were developed to dissect immunoregulatory mechanisms involved in CMA and the role of the normal absorptive epithelium (E loops) vs the M cells and associated Peyer's patches in (M loops) in the development of tolerance. The combined resources of this program project provide a unique opportunity to define the immunologic bases for four common forms of CMA. Building on the well-defined patient cohorts enrolled in the program, the first project will further investigate unique humoral and cellular mechanisms underlying these disorders and changes associated with the development of clinical tolerance. The second project will focus on the function of intestinal epithelial cell CD23 as a bi-directional transporter of IgE and its role in CMA. The third project will utilize a novel in vivo gut-loop model to dissect immunologic mechanisms associated with the induction of normal gut-associated tolerance and pathologic responses of CMA. The fourth project will further investigate pathogenic immunoregulatory responses in murine models of CMA and cow milk tolerance, and evaluate the use of""""""""engineered"""""""" recombinant proteins [from information gleaned in Project #1 ] to reverse CMA in mice with milk-induced anaphylaxis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI044236-07
Application #
6889903
Study Section
Special Emphasis Panel (ZAI1-GB-I (M1))
Program Officer
Plaut, Marshall
Project Start
2000-08-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
7
Fiscal Year
2005
Total Cost
$1,111,117
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Nowak-W?grzyn, Anna; Lawson, Kaitie; Masilamani, Madhan et al. (2018) Increased Tolerance to Less Extensively Heat-Denatured (Baked) Milk Products in Milk-Allergic Children. J Allergy Clin Immunol Pract 6:486-495.e5
Frischmeyer-Guerrerio, Pamela A; Masilamani, Madhan; Gu, Wenjuan et al. (2017) Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol 140:1043-1053.e8
Wood, Robert A; Kim, Jennifer S; Lindblad, Robert et al. (2016) A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy. J Allergy Clin Immunol 137:1103-1110.e11
Järvinen, Kirsi M; Suárez-Fariñas, Mayte; Savilahti, Erkki et al. (2015) Immune factors in breast milk related to infant milk allergy are independent of maternal atopy. J Allergy Clin Immunol 135:1390-3.e1-6
Lee, Tricia D; Gimenez, Gustavo; Grishina, Galina et al. (2015) Profile of a milk-allergic patient who tolerated partially hydrolyzed whey formula. J Allergy Clin Immunol Pract 3:116-8
Järvinen, 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; Masilamani, Madhan; Rivers, Neisha A et al. (2014) Potential non-T cells source of interleukin-4 in food allergy. Pediatr Allergy Immunol 25:243-9
Tordesillas, Leticia; Goswami, Ritobrata; Benedé, Sara et al. (2014) Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest 124:4965-75
Roda, G; Jianyu, X; Park, M S et al. (2014) Characterizing CEACAM5 interaction with CD8? and CD1d in intestinal homeostasis. Mucosal Immunol 7:615-24
Järvinen, Kirsi M; Konstantinou, George N; Pilapil, Mariecel et al. (2013) Intestinal permeability in children with food allergy on specific elimination diets. Pediatr Allergy Immunol 24:589-95

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