Targeting Kit Activation: A Potential Therapeutic Approach in the Treatment of Allergic Inflammation
Bettina M. Jensen, Dean D. Metcalfe and Alasdair M. Gilfillan
Affiliation: Laboratory of Allergic Diseases,National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C206, LAD, NIAID, NIH, 10 Center Drive, Bethesda, MD 20892-1881, USA.
Keywords: Mast cell, Kit, stem cell factor, allergic inflammation, imatinib mesylate, tyrosine kinase inhibitor
The prevalence of allergic diseases is increasing worldwide. Hence, there is continued need for novel pharmacological therapies for the treatment of these disorders. As the mast cell is one of the essential cells that contributes to the inflammation associated with allergic diseases, this cell type remains an attractive target for such pharmacological intervention. Mast cells are major players in the early phase of the allergic response since they generate and release a variety of inflammatory mediators following antigen-dependent aggregation of IgE-bound Fc??RI (high affinity IgE-receptor) on the cell surface. These mediators also contribute to the late and chronic stages of allergic inflammation. Thus, the IgE/antigen response has been a major focus in the development of new drugs targeting mast cells. The essential role that stem cell factor (SCF) and its receptor, Kit, play in mast cell biology, however, may provide us with an alternative or adjunct therapy. SCF is necessary for mast cell development, proliferation and survival, but it is also known to play a role in homing and adhesion of mast cells. Furthermore, there is an increasing amount of literature demonstrating that SCF is necessary for optimal IgE/antigen-induced mast cell degranulation and cytokine production. Several drug candidates targeting SCF and/or Kit have been studied for their anti-allergic properties. These include anti-SCF antibodies, antisense oligonucleotides, Kit inhibitors, and inhibitors of downstream signaling molecules. In this review, we provide an overview of the role of SCF and Kit in mast cell activation and discuss potential drug candidates for targeting this response.
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