Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo
| Autor: | Shih-Yao Lin, Stefan Kraft, Peter Storz, M H Jouvin, James M. Billingsley, Tony Fleming, Jean-Pierre Kinet |
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| Rok vydání: | 2005 |
| Předmět: |
Serotonin
Immunology Platelet Membrane Glycoproteins Immunoglobulin E Article Cell Line Extracellular matrix 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tetraspanin Antigens CD Cell Adhesion Hypersensitivity Animals Humans Immunology and Allergy Mast Cells Vitronectin Phosphorylation Cell adhesion Protein Kinase C Adaptor Proteins Signal Transducing 030304 developmental biology 0303 health sciences biology Receptors IgE Tetraspanin 30 Passive Cutaneous Anaphylaxis Degranulation Antibodies Monoclonal Fibrinogen Tyrosine phosphorylation Phosphoproteins Molecular biology Fibronectins Rats 3. Good health Cell biology Fibronectin Protein Kinase C-delta chemistry 030220 oncology & carcinogenesis biology.protein Tyrosine Calcium Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20042085 |
| Popis: | High-affinity IgE receptor (FcepsilonRI) cross-linking on mast cells (MCs) induces secretion of preformed allergy mediators (degranulation) and synthesis of lipid mediators and cytokines. Degranulation produces many symptoms of immediate-type allergic reactions and is modulated by adhesion to surfaces coated with specific extracellular matrix (ECM) proteins. The signals involved in this modulation are mostly unknown and their contribution to allergic reactions in vivo is unclear. Here we report the generation of monoclonal antibodies that potently suppress FcepsilonRI-induced degranulation, but not leukotriene synthesis. We identified the antibody target as the tetraspanin CD63. Tetraspanins are membrane molecules that form multimolecular complexes with a broad array of molecules including ECM protein-binding beta integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits FcepsilonRI-mediated degranulation in cells adherent to those ECM proteins but not in nonadherent cells. Thus the inhibition of degranulation by anti-CD63 correlates with its effect on adhesion. In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcepsilonRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2-PI3K pathway that is known to be essential for both degranulation and adhesion. Finally, we showed that these antibodies inhibited FcepsilonRI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases. |
| Databáze: | OpenAIRE |
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