These results demonstrate the potential of a combined KIT/Fc?RI inhibition in the treatment of allergic diseases. Mast cells have been implicated in the pathogenesis of rheumatoid arthritis (Malone em et al /em ., 1986, 1987; Malone and Metcalfe, 1988), and a recent study (Juurikivi em et al /em ., 2005) revealed that imatinib effectively induces mast cell apoptosis and reduces TNF- production in human synovial tissue cultures. multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders. oncogene, which is mapped to the locus in the mouse, encodes for a protein, KIT (CD117), which is a member of the transmembrane receptors with tyrosine kinase activity superfamily. This family also includes other growth factor receptors, namely FMS-like tyrosine kinase 3 (FLT3), the platelet-derived growth factor receptor (PDGFR), and the macrophage colony stimulating factor (M-CSF) receptor (Broudy, 1997; Patnaik and culture systems (Kirshenbaum is currently unknown. In addition to its ability to regulate mast cell homeostasis and tissue distribution, SCF is also recognized as a potent modifier of mast cell activation. When triggered, mast cells release an array of inflammatory mediators that contribute to the initiation of anaphylaxis and the inflammatory reactions associated with the asthmatic response (Metcalfe has yet to be determined. KIT and mast cell disorders Although KIT is a critical molecule in haematopoesis, gametogenesis, and mast cell development, activating mutations resulting in ligand-independent autophosphorylation may lead to dysregulated growth of the affected cells, thereby inducing tumourogenesis (Akin and Metcalfe, 2004). Diseases such as gastrointestinal stromal tumours, systemic mastocytosis, germ cell tumours and core factor binding acute myeloid leukaemias carry mutations in KIT (Patnaik studies showed that D816V KIT was able to confer growth factor independence to transformed haematopoietic cell lines (Kitayama studies, it would be logical to assume that an activating mutation in KIT would result in exaggerated antigen-mediated mast cell activation. Surprisingly, one study using mismatch amplification real-time PCR assay found a relatively high occurrence of the D816V mutation (2 out of 9, 22%) in subjects without a history of atopy or anaphylaxis (Lawley kinase assay (Schirmer experiments performed with mononuclear cells obtained from the bone marrow of patients with systemic mastocytosis showed that tyrosine kinase inhibitors effective against D816V KIT cause TMOD4 preferential cytotoxicity of mast cells carrying this mutation over other mononuclear cells (Akin without toxicity to other tissues. This problem may be particularly pertinent for non-specific inhibitors with multiple targets. The proof of concept that a KIT inhibitor can indeed cause regression of mastocytosis driven by a KIT mutation resulted from a study in which a patient with an unusual activating KIT mutation was treated with imatinib, and achieved complete remission (Akin hybridization or by reverse transcription-PCR), leading to constitutive activation of the intrinsic tyrosine kinase activity of PDGFRA. These patients, who have a multilineage myeloproliferative disorder that involves mast cell as well as eosinophil progenitors, are generally male, display organ pathology due to eosinophilia and do not have the characteristic D816V KIT mutation observed in other MRS1186 categories of mastocytosis (Klion data mentioned above as well as our personal experience (Cem Akin), our current practice is not to treat patients with codon 816 KIT mutations with imatinib. Clinical trials with other KIT inhibitors have largely yielded disappointing results. In a phase-2 trial of nilotinib, among 60 patients (83% positive for D816V KIT) treated with 400?mg twice daily dose of nilotinib, only 2 showed complete remission (Hochhaus activity of nilotinib on D816V KIT (Verstovsek data obtained so far appear promising. Combination of dasatinib with midostaurine or cladribine yielded synergistic effects in HMC-1.2 mast cells carrying the D816V c-KIT mutation (Gleixner passive cutaneous anaphylaxis in mice. These results demonstrate the potential of a combined KIT/Fc?RI inhibition in the treatment of MRS1186 allergic diseases. Mast cells have been implicated in the pathogenesis of rheumatoid arthritis (Malone em et al /em ., 1986, 1987; Malone MRS1186 and Metcalfe, 1988), and a recent study (Juurikivi em et al /em ., 2005) revealed that imatinib effectively induces mast cell.