High dose exposure to the major cat allergen, Feld 1, has been associated with a paradoxical decrease in sensitization. Many children who are exposed to high levels of cat allergen (>=20mu/g/g dust), but who are not allergic, have a serologic profile (IgG pos IgE/neg) that is distinct from allergic subjects (IgG p?s IgEP?S); this has been described as a modified Th2 response. Such """"""""high dose"""""""" tolerance could explain the decrease in asthma among subjects living with a cat. Regulatory T cells induced by high dose natural exposure to allergens commonly associated with asthma have not been studied. Novel CD4+ T cell major epitopes ofFel d 1 chain 2 which selectively induce IL-10 and IFN-gamma (peptides 2:1and 2:2) have been implicated in tolerance induced during immunotherapy (IT) for cat. T cell reactivity to these epitopes is diminished in highly allergic patients with atopic dermatitis (AD)(mean IgE ab to cat -- 21 IU/ml) compared to patients with a modified Th2 response who express the major HLA-DR allele """"""""0701. In the proposed studies, the relevance of regulatory cytokines (IL-10 and TGF-[3) to Fel d 1-specific CD4+ T cell responses will be investigated using cultures stimulated with overlapping peptides of Fel d 1. Subjects studied will include allergic patients with and without AD, DR7+ and DR7- modified Th2 responders, and control (IgG neg IgE neg) subjects. Additional mediators of tolerance will be sought using antibody-based protein arrays. Patients receiving high dose IT for cat will be included in order to compare systemic (IT) and inhalational (modified Th2) tolerance and T cell epitopes relevant to systemic tolerance will be studied by monthly monitoring of patients starting IT. The relevance of chain 2 epitope-specific T cells to the modified Th2 response will be studied using MHC restriction analysis, by enumerating cells using ELISPOT assay, and by studying phenotypic characteristics using flow cytometry. Effects of regulatory cytokines on epitopespecific T cell responses will be examined and tissue-specific homing of Feld 1-specific cells to the lungs (asthmatic subjects), gut (modified Th2) or skin (AD) will also be analyzed. The natural forms of chain 2 epitopes will be identified from peptide mixtures on the surface of antigen presenting cells using mass spectrometry. Finally, given the evidence that CD8+ T cells may also target chain 2 epitopes, the ability for class I MHC peptides of Fel d 1 to induceCD8+ T cell responses in vitro will be examined and epitope-specific CD8+ T cells will be analyzed by peptide-MHC tetramer staining. Defining cellular mechanisms which govern tolerance to cat is fundamental to understanding the factors that control the prevalence and severity of asthma and to the rational design of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052196-04
Application #
7227798
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Minnicozzi, Michael
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$253,046
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wisniewski, Julia A; Muehling, Lyndsey M; Eccles, Jacob D et al. (2018) TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J Allergy Clin Immunol 141:2048-2060.e13
Wisniewski, J A; Commins, S P; Agrawal, R et al. (2015) Analysis of cytokine production by peanut-reactive T cells identifies residual Th2 effectors in highly allergic children who received peanut oral immunotherapy. Clin Exp Allergy 45:1201-13
Romeo, Martin J; Agrawal, Rachana; Pomés, Anna et al. (2014) Reply: To PMID 24084078. J Allergy Clin Immunol 134:762-3
Agrawal, R; Wisniewski, J; Yu, M D et al. (2014) Infection with human rhinovirus 16 promotes enhanced IgE responsiveness in basophils of atopic asthmatics. Clin Exp Allergy 44:1266-73
Agrawal, Rachana; Woodfolk, Judith A (2014) Skin barrier defects in atopic dermatitis. Curr Allergy Asthma Rep 14:433
Romeo, Martin J; Agrawal, Rachana; Pomés, Anna et al. (2014) A molecular perspective on TH2-promoting cytokine receptors in patients with allergic disease. J Allergy Clin Immunol 133:952-60
Wisniewski, J A; Agrawal, R; Minnicozzi, S et al. (2013) Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis. Clin Exp Allergy 43:1160-70
Wisniewski, J; Agrawal, R; Woodfolk, J A (2013) Mechanisms of tolerance induction in allergic disease: integrating current and emerging concepts. Clin Exp Allergy 43:164-76
Agrawal, Rachana; Wisniewski, Julia A; Woodfolk, Judith A (2011) The role of regulatory T cells in atopic dermatitis. Curr Probl Dermatol 41:112-24
Reefer, Amanda J; Hulse, Kathryn E; Lannigan, Josephine A et al. (2010) Flow cytometry imaging identifies rare T(H)2 cells expressing thymic stromal lymphopoietin receptor in a ""proallergic"" milieu. J Allergy Clin Immunol 126:1049-58, 1058.e1-10

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