>>Am J Respir Cell Mol Biol. 2005 Dec 9; [Epub ahead of print]
Syk Activation in Dendritic Cells is Essential for Airway Hyperresponsiveness and Inflammation.
Matsubara S, Koya T, Takeda K, Joetham A, Miyahara N, Pine P, Masuda ES, Swasey CH, Gelfand EW.
Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO, USA.
In this study, we evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be both B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum following 3 consecutive OVA challenges resulted in AHR to inhaled methacholine (MCh) and airway inflammation. The Syk inhibitor R406 (30 mg/kg, p.o., b.i.d.) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and prior to challenge with OVA. Levels of IL-4, IL-5 and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. As many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDCs) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pre-treated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not non-pulsed BMDCs) to naive mice prior to airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pre-treated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation following systemic sensitization and challenge, at least in part through alteration of DC function.<<
Target druggable? Seems so, given the PII & other data. The PIII endpoint was just ambitious (longer duration) for this formulation. The above provides some further validation for the target.
Cheers, Tuck |
