Cytokine Signalling Forum

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The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4+T cell-priming capacity of dendritic cells

Platt AM, Benson RA, McQueenie R, et al. - Rheumatology (Oxford). 2015;54(1):169–177

SYK is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors. While the clinical development of the first SYK inhibitor, fostamatinib, was stopped due to poor results in the phase 3 RA programme, there remain important questions of mechanism which may aid future developments of this target.

In these murine studies, investigators sought to gain an understanding of how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level, by studying the effects of fostamatinib on antigen-specific interactions between dendritic cells (DC) and CD4+ T cells.

There are several key rheumatology findings from this study; fostamatinib fails to block CD4+ T cell priming in response to immune complexes; R406 inhibits DC stimulatory capacity; CD4+ T cells primed with R406-treated DCs fail to undergo proliferation or functional maturation.

The authors speculate that some of the in vitro effects may be translated in vivo if the correct locale and concentration can be achieved.