Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-10-08
2000-03-07
Adams, Donald E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
530350, 435 691, 4351723, C07H 2102, C07K 100, C12P 2106, C12N 1500
Patent
active
060342277
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is generally in the field of inflammation and allergy and relates to substances which may be useful in controlling the cellular processes which result in inflammation or allergic reactions. More specifically, the present invention concerns a new isolated DNA molecule encoding a protein, the mast cell function-associated antigen (hereinafter MAFA), which is capable of modulating the response to the type I Fc.epsilon. receptor for IgE (hereinafter Fc.epsilon.RI), which is present on the surface of mast cells, basophils, eosinophils and Langerhans cells, and which activates these cells. The present invention also concerns recombinant expression vectors containing the MAFA-encoding DNA molecule and host cells transformed by the vectors which are capable of expressing biologically active MAFA. The invention also provides a method for screening potential ligands of MAFA, which ligands alone or in combination with MAFA may be used to prevent inflammation and allergy.
BACKGROUND OF INVENTION AND PRIOR ART
Mast cells and basophils are immunologically activated by aggregation of IgE molecules bound to the Fc.epsilon.RI with multivalent antigen. Cell response can also be induced by directly cross-linking the Fc.epsilon.RI, for example, with anti-receptor antibodies. Clustering of the Fc.epsilon.RI on mast cells and basophils by either IgE and polyvalent antigen or directly by specific monoclonal antibodies, initiates a cascade of biochemical processes coupling to the cells secretory response. These include: (i) the activation of receptor-associated protein tyrosine kinases (Eiseman and Bolen, 1992) and phosphatases (Hampe and Pecht, 1994) causing a transient increase in tyrosine phosphorylation of several cellular proteins (Benhamou et al., 1990 and 1992); (ii) an increase in phosphoinositides hydrolysis (Beaven et al., 1984a) resulting from PLC.gamma.1 activation (Li et al., 1992); and (iii) the rise in the intracellular concentration of free calcium ions (Beaven et al., 1984b). The final response to this stimulus is the secretion of granule-stored mediators and the de novo synthesis and secretion of mediators of inflammation and the allergic response, including histamine, serotonin, arachidonic acid metabolites, like leukotrienes (Ortega et al., 1989), prostaglandins, and several cytokines (Bradding et al., 1993; Galli et al., 1991).
Several mast cell membrane components different from known Fc.epsilon.RI subunits have been identified on the rat mucosal type mast cell line RBL-2H3, mainly by specific monoclonal antibodies (mAb), and shown to modulate the Fc.epsilon.RI-mediated secretory response. G63, a mAb that binds a membranal glycoprotein named MAFA, for mast cell function-associated antigen (Ortega and Pecht, 1988), was shown to inhibit both the Fc.epsilon.RI-induced signalling cascade upstream to PLC.gamma.1 activation (e.g. phosphatidylinositide hydrolysis products and transient rise in the cytoplasmic concentration of free Ca.sup.2+ ions), and the culminating secretion of the cells' granule contents (Ortega and Pecht, 1988). mAb G63 inhibitory effect required MAFA clustering, and was not due to interference with IgE- Fc.epsilon.RI interactions. Still, cross-linking of Fc.epsilon.RI-IgE complexes by multivalent antigen also led to co-clustering of the MAFA with the aggregated Fc.epsilon.RI and in the enhancement of its internalization (Ortega et al., 1991).
The MAFA has been identified as a glycoprotein with a MW of 28 to 40 kDa distinct from any known Fc.epsilon.RI subunit by immunoprecipitation with mAb G63 and reducing SDS-PAGE. When the SDS-PAGE was run under non-reducing conditions, the observed pattern was different: a component with an apparent MW of 60-82 kDa was detected in addition to the above described 28 to 40 kDa band, suggesting that the MAFA is a disulfide-linked dimer composed of subunits of similar size (Ortega and Pecht, 1988).
Following the discovery of MAFA, the present inventors sought to isolate and sequence the gene encoding this protei
REFERENCES:
patent: 4683135 (1987-07-01), Pecht et al.
Ortega Sote et al., "A Monoclonal Antibody that Inhibits Secretion from Rat Basophilic Leukemia Cells and Binds to a Novel Membrane Component", Journal of Immunology, vol. 141, No. 12, pp. 324-4332 Dec. 15, 1988.
Ortega et al., "Possible Interactions between the Fc(epsilon) Receptor and a Novel Mast Cell Function-Associated Antigen", International Immunology, vol. 3, No. 4, pp. 333-342 (1991).
Soto et al., 1988, J. Immunol. 141:4324-4332.
Ortega et al., 1991, Internatl. Immunol. 3:333-342.
Guthmann Marcelo D.
Pecht Israel
Tal Michael
Adams Donald E.
Parkin Jeffrey S.
Yeda Research and Development Co. Ltd.
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