Chemistry: analytical and immunological testing – Food or dairy products – Dairy product
Reexamination Certificate
1999-01-28
2001-05-29
Wessendorf, T. (Department: 1627)
Chemistry: analytical and immunological testing
Food or dairy products
Dairy product
C436S022000, C436S021000, C436S020000, C436S543000, C435S007100, C435S004000, C424S185100, C424S184100
Reexamination Certificate
active
06238925
ABSTRACT:
BACKGROUND OF THE INVENTION
Hypersensitivity reactions to foods affect up to 6% of children in the first few years of life (Bock, S. A. 1987.
Pediatrics
79:683-688), with milk, egg, and peanut accounting for most of the documented allergic responses (James J M and Sampson H A. 1992.
Pediatr Allergy & Immunol
3:67-78). Most milk-allergic children develop cow milk hypersensitivity in the first year of life and then approximately 80% “outgrow” their reactivity (i.e. become clinically tolerant) by three years of age (Host, A. 1994.
Pediatr Allergy Immunol
5:5-36). Hypersensitivity to hen's egg and peanut are more often recognized in the second year of life. Egg allergy appears to be more persistent than cow milk allergy whereas peanut allergy is very rarely “outgrown” (Bock, S. A. 1982.
J Allergy Clin Immunol
69:173-177; Sampson, H. A. and S. M. Scanlon. 1989.
J Pediatr
115:23-27; Bock, S. A. and F. M. Atkins. 1989.
J Allergy Clin Immunol
83:900-904). The basis for these differences in persistence of clinical hypersensitivity to different food allergens is unknown.
Egg allergy is present in nearly two-thirds of children with atopic dermatitis (Sampson, H. A. J. 1997
Roy. Soc. Med.
90(suppl 30):3-9). When egg allergic children are placed on a diet devoid of all egg protein, about one-third develop clinical tolerance to egg within 2 years, even though IgE antibodies to egg (e.g. positive prick skin tests) persist for several years (Sampson 1989). Ovomucoid (Gal d 1) is the dominant allergen in hen's egg, and children with persistent egg allergy have significantly higher concentrations of IgE anti-ovomucoid antibodies than those who “outgrow” their reactivity (Bernhisel-Broadbent, J.,et al. 1994.
J Allergy Clin Immunol
93:1047-1059). Ovomucoid is a glycoprotein comprised of 186 amino acids arranged in three tandem domains containing nine intra-domain disulfide bonds and five carbohydrate side chains (Kato, et al. 1987.
Biochemistry
26:193-201).
It is an object of this invention to provide an assay including methods and reagents for predicting the likelihood that children will outgrow an allergy, especially a food allergy.
It is a further object of the present invention to provide a method and reagents to screen for the presence of antibodies to linear versus conformational epitopes in patient samples.
SUMMARY OF THE INVENTION
Methods and reagents are provided for use in predicting the likelihood a child will outgrow an allergy, especially a food allergy, by screening for the immunoreactivity of IgE antibodies with linear epitopes as compared to conformational epitopes. The child is first screened using standard techniques to determine what antigens the child is allergic to. The immunoglobulins in the sample from the patient are then characterized either using the natural purified antigen, recombinant antigen, reduced and alkylated antigen, proteolytic fragments of the antigen or synthetic peptides of between four and 40 amino acids in length, preferably six to ten amino acids, which can be immobilized for rapid and accurate screening. The antibodies from the patient, typically present in a serum or plasma sample, are reacted with the protein or peptides to determine which peptides are bound by the antibodies. These antibodies are then characterized to determine if the epitopes they bind are linear or conformational. Those patients having antibodies primarily reactive with conformational epitopes (that is, reactive with native protein or proteolytic fragments, as compared to reduced and alkylated protein or synthetic linear peptides) will typically outgrow their allergies. Those that are reactive primarily with linear epitopes may not outgrow their reactivity and may need to be treated to induce tolerance.
The method for screening is demonstrated in an example utilizing pooled sera from egg-allergic patients and overlapping synthetic decapeptides derived from the sequence for ovomucoid. Ovomucoid was found to possess five allergenic IgE-binding epitopes. Evaluating allergenic epitopes with individual patient sera revealed three patterns of epitope binding: extensive IgE binding to decapeptides in all three ovomucoid domains, IgE binding predominantly to peptides in the first domain, and virtually no IgE binding to any synthetic peptides, indicating that most IgE antibodies in the latter group recognized conformational epitopes. All patients had extensive IgG antibody binding to the linear, synthetic peptides whereas all non-egg allergic controls recognized only conformational epitopes. Patients in the group with extensive IgE binding to linear decapeptides tended to be older and have more severe, generalized allergic symptoms following egg ingestion than the patient group with little IgE antibody to synthetic peptides. These findings indicate that differential antigen processing and antibody-epitope structural recognition play a role in the clinical course of allergen sensitivity.
A similar method for evaluation of IgG antibodies can be used to predict the prognosis of certain inflammatory disorders, especially those involving the gastrointestinal tract such as Crohn's disease, ulcerative colitis, and celiac disease.
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Bernhisel-Broadbent, et al., “Allergenicity and antigenicity of chicken egg ovomucoid (Gal d III) compared with ovalbumin (Gal d I) in children with egg allergy and in mice,”J Allergy Clin Immunol93:1047-1059 (1994).
Bernhisel-Broadbent, et al., “Cross-allergenicity in the legume botanical family in children with food hypersensitivity. II. Laboratory correlates”J Allergy Clin. Immunol.84:701-709 (1989).
Bock & Atkins, “The Natural history of peanut allergy,”J. Allergy Clin. Immunol83: 900-904 (1989).
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Kato, et al., “Chicken ovomucoid: determination of its amino acid sequence, determination of the trypsin reactive site, and preparation of all three of its domains,”Biochemistry26:193-201 (1987).
Kletter, et al., “Immune responses of normal infants to cow milk. I. Antibody type and kinetics of production,”Int Arch Allergy Appl Immunol40:656-666 (1971).
Laffer, et al., “Molecular characterization of Bip 1, a monoclonal antibody that modulates IgE binding
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Panacea Pharmaceuticals, LLC
Wessendorf T.
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