Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivityreactions and anaphylaxis

Janus kinase 3 (JAK3), a member of the Janus family protein-tyrosine kinase s, is expressed in mast cells, and its enzymatic activity is enhanced by Ig E receptor/Fc epsilon RI cross-linking Selective inhibition of JAK3 in mast cells with 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline) (WHI-P131 ) blocked the phospholipase C activation, calcium mobilization, and activat ion of microtubule-associated protein kinase after IgE receptor/Fc epsilon RI cross-linking. Treatment of IgE-sensitized rodent as well as human mast cells with WHI-P131 effectively inhibited the activation-associated morphol ogical changes, degranulation, and proinflammatory mediator release after s pecific antigen challenge without affecting the functional integrity of the distal secretory machinery. In vivo administration of the JAK3 inhibitor W HI-P131 prevented mast cell degranulation and development of cutaneous as w ell as systemic fatal anaphylaxis in mice at nontoxic dose levels. Thus, JA K3 plays a pivotal role in IgE receptor/Fc epsilon RI-mediated mast cell re sponses, and targeting JAK3 with a specific inhibitor, such as WHI-P131, ma y provide the basis for new and effective treatment as well as prevention p rograms for mast cell-mediated allergic reactions.