The Journal of Experimental Medicine
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Published online 31 January 2005 doi:10.1084/jem.20042085
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 3, 385-396
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ARTICLE

 Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo

Stefan Kraft, Tony Fleming, James M. Billingsley, Shih-Yao Lin, Marie-Hélène Jouvin, Peter Storz, and Jean-Pierre Kinet

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

CORRESPONDENCE Jean-Pierre Kinet: jkinet{at}bidmc.harvard.edu

High-affinity IgE receptor (Fc{varepsilon}RI) 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 Fc{varepsilon}RI-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 ß integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits Fc{varepsilon}RI-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 Fc{varepsilon}RI-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 Fc{varepsilon}RI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases.

Abbreviations used: DNP-HSA, DNP-human serum albumin; ECM, extracellular matrix; Fc{varepsilon}RI, high affinity IgE receptor; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; LTC4, leukotriene C4; MC, mast cell; PCA, passive cutaneous anaphylaxis; PI3K, phosphatidylinositol-3 kinase; PI4K, phosphatidylinositol-4 kinase; PKC{delta}, protein kinase C-{delta}; PTK, protein– tyrosine kinase; RBL, rat basophilic leukemia.


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