Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1999-02-17
2001-08-07
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S184100, C435S007100, C436S513000
Reexamination Certificate
active
06270746
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of immunosuppressive drugs and screening assays for their identification. More specifically, the invention relates to a screening assay for use in identifying agents which suppress, selectively or non-selectively, the synthesis or activity of antibodies of the immunoglobulin E isotype (IgE).
HISTORY OF THE RELATED ART
IgE antibodies mediate aspects of the mammalian immune response to antigens which contribute toward the onset of an allergic attack. In susceptible individuals, IgE can induce a hypersensitive phenotype involving the excessive and rapid release of mediators such as histamine, slow-reacting substance of anaphylaxis and eosinophilic chemotactic factor leading, in the extreme, to potentially fatal conditions such as anaphylaxis.
Control of the IgE mediated immune response is therefore an important goal of allergy therapy, especially in immunotherapies directed to the induction of antigen tolerance through repeated antigen challenge of the host immune system. For the purposes of allergy therapy, the challenge is to suppress the host immune system in a manner which dampens the activity of IgE while retaining the protective and otherwise beneficial effects of all of the host other immune response to particular antigens. Thus, immunosuppressive agents which selectively target IgE mediated immune responses are potentially potent weapons in the arsenal against allergic disease.
SUMMARY OF THE INVENTION
The invention provides an screening assay for use in identifying agents which have potential for pharmaceutical use as suppressors of IgE mediated, antigen-specific immune responses to antigens. For use in the assay, an animal which hyper responds to antigen by producing exaggerated levels of IgE is prepared or otherwise obtained. Initial sensitization of the animal to antigen is made within a specific, time-limited window of sensitivity defined by the invention. The animal thereafter maintains exaggerated IgE responsiveness to the sensitizing antigen, despite its return to an otherwise normal IgE phenotype.
Identification of potential IgE suppressors is performed in the animal by treating it with the candidate suppressor with or following primary immunization. A decline in antigen-specific IgE levels following treatment indicates that the candidate possesses suppressive activity. The scope of useful information provided by the assay can be expanded through measurement and comparison of other indicia of IgE immune responsiveness in the animal, such as levels of markers of the Th2 immunophenotype in which IgE production is normally induced.
To these ends, in one aspect of the invention, the animal platform for the screening assay is a non-human mammal whose IgE-mediated allergic system correlates with the IgE-mediated allergic systems of humans.
In another aspect of the invention, the non-human mammal is a rodent.
In another aspect of the invention, the rodent is a mouse.
In another aspect of the invention, the animal platform is rendered hyper responsive to antigen through low dose irradiation.
In another aspect of the invention, successful induction of an IgE hyperresponsive phenotype in the animal platform for the screening assay is confirmed through ablation of such responsiveness with CD23
+
B cells delivered to the animal during the window of sensitivity defined by the invention.
REFERENCES:
Katz et al. Clinnical Allergy 9:609-624.*
Kerdine et al. Molecular Immunology 33(1):71-77.*
Bargate & Katz,“′Allergic Breakthrough′after antigen sensitization: height of IgE synthesis is temporally related to diurnal variation in endogenous steroid production,”J. Immunol.1980;125(5):2306-2310.
Bellanti, J.A., “Cytokines and allergic diseases: clinical aspects.”Allergy Asthma Proc1998;19(6):337-41.
Blaser, et al., “Investigation of a syngeneic murine model for the study of IgE antibody regulation with isologous antiidiotype antibodies,”Int Arch Allergy Appl Immunol, 1981;64(1):42-50.
Chen, et al., “A Mouse Model of Mosquito Allergy for Study of Antigen-Specific IgE and IgG Subclass responses, Lymphocyte Proliferation, and IL-4 and IFN-&ggr;Production,”Int. Arch. Allergy Immunol.1998;116:269-277.
Choi, et al. “Immunoglobulin E-dependent active fatal anaphylaxis in mast cell-deficient mice,”J Exp Med, 1998;188(9):1587-92.
Chua, et al., “Epression ofDermataphagoides pteronyssinusAllergen, Der p II, inEscherichia coliand the Binding Studies with Human IgE,”Int. Arch. Allergy Appl. Immunol.1990;91:124-129.
Chua, et al., “Sequence Analysis of cDNA Coding for a Major House Dust Mite Allergen, Der p I Homology with Cysteine Proteases,” J. Exp. Med 1988;167:175-182.
Claman, et al., “Immunoglobulin Dysregulation in Murine Graft-vs-Host Disease: A Hyper-IgE Syndrome.”Clin Immunol Immunopathol1990;56(1):46-53.
Cooper, D.A., “The immunological basis of immediate hypersensitivity,”Aust Fam Physician,1979;8(1):38-39, 41-43, 45-46.
Diaz-Sanchez, et al., “Ricin enhances IgE responses by inhibiting a subpopulation of early-activated IgE regulatory CD8+T cells,”Immunol, 1993;78(2):226-36.
Dombrowicz, et al., “Anaphylasix Mediated Through a Humanized High Affinity IgE Receptor,”J. Immunol.1996;15:1645-1651.
Fung-Leung, et al., “Transgenic Mice Expressing the Human High-Affinity Immunoglobulin (Ig) E Receptor &agr;Chain Respond to Human IgE in Mast Cell Degranulation and in Allergic Reactions,”J Exp Med1996;183(1):49-56.
Katz, et al., “Regulation of IgE antibody production by serum molecules. V. Evidence that coincidental sensitization and imbalance in the normal damping mechanism results in ′allergic breakthrough,′”J. Immunol., 1979;122(6)2191-2197.
Katz, et al., “The IgE antibody system: mature, peripheral B lymphocytes exert regulatory influences on the IgE systems of self-reconstituting, sublethally irradiated mice.”J Mol Cell Immunol, 1984;1(2)83-9.
Katz, “IgE Antibody Responses in vitro: from Rodents to Man,”Prog. Allergy1982;32:105-160.
Kawabata, et al., “Measurement of murine ovalbumin-specific IgE by a rat basophil leukemia cell serotonin release assay. Comparison to the rat passive cutaneous anaphylaxis assay.”j Immunol Methods, 1993;162(1):9-15.
Marcelletti, et al., “IL-10 Stimulates Murine Antigen-Driven Antibody ResponsesIn Vitroby Regulating Helper Cell Subset Participation.”Cell Immunol, 1996;167(1):86-98.
Marcelletti, et al., “The Cellular Lesion Responsible for Exaggerated IgE Synthesis Accompanying Allergic Breakthrough.”Cell Immunol, 1989;120(2):314-29.
Ohta, et al., “Human tonsillar IgE biosynthesis in vitro. I. Enhancement of IgE and IgG synthesis in the presence of pokeweed mitogen by T-cell irradiation,”J. Allergy Clin. Immunol.1983;7:212-223.
Peeters, et al., “Regulation of the IgE antibody response in Mice. II. Radioresistance of established IgE antibody production.”Immunol1981;43(1):25-32.
Rafnar, et al., “Cloning ofAmb aI (Antigen E), the Major Allergen Family of Short Ragweed Pollen*”J. Biol. Chem.1991;266:1229-1236.
Richards & Katz, “Analysis of the Promoter Elements Necessary for IL-4 and Anti-CD40 Antibody Induction of Murine FceRII (CD23),”J.Immunol.1997;158:263-272.
Rizzo, et al., “Differential regulation of antigen presentation in high-and low-IgE responder mice,”Eur J Immunol, 1991;21(7):1767-70.
Rogers, et al., “Recombinant Fel d I: Expression, Purification, IgE Binding and Reaction with Cat-Allergic Human T Cells,”Mol. Immunol.1993;30:559-568.
Santos-Argumendo, et al., “Antibodies to Murine CD40 Protect Normal and Malignant B Cells from Induced Growth Arrest,”Cell Immunol, 1994;156(2):272-85.
Van Neerven, et al., “t Cell Epitopes of House Dust Mite Major allergenDer pII,”J. Immunol1993;151:2326-2335.
Vriesendorp, et al., “Immunoglobulin Levels in Dogs after Total-Body Irradiation and Bone Marrow Transplantation,”Transplantation1985;39:583-588.
Yang, et al., “CD8+T cells inhibit immunoglobulin E synthesis inlow responder SJL/J mice,”Immunol., 1998;93(2):230-237.
DeCloux Amy
Foley & Lardner
Saunders David
Taylor Stacy L.
LandOfFree
Assay for the identification of IgE antibody suppressors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Assay for the identification of IgE antibody suppressors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Assay for the identification of IgE antibody suppressors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2480771