Abstract
Background/Purpose
Spleen tyrosine kinase (SYK) is a core signaling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune-receptors including the B cell
receptor (BCR) and Fc receptors (FcRs). The small molecule SYK inhibitor, fostamatinib, has shown evidence of ameliorating inflammation in rheumatoid arthritis (RA) patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level. It has been shown that R406 reduces the response of dendritic cells (DCs) to immune complexes (ICs) and we have previously demonstrated that the area and duration of interaction between T cells and DCs are key
determinants in the outcome of an immune response.
MethodsFluorescence microscopy was combined with CD4 T cells from T cell receptor transgenic OT-II mice to track antigen-specific interactions
between DCs and T cells in vitro.
ResultsWe have found that R406 reduces the DC-T cell contact area and the number of interactions lasting more than 5 minutes during the initial
phase of cellular cross-talk between IC-activated DCs and antigen-specific CD4 T cells. This led to diminished proliferation with 19.20.5% of OT-II CD4 T cells undergoing proliferation (and only a maximum of two rounds) after R406 treatment compared with 79.62.0% in vehicle controls. This reduced proliferative capacity of CD4 T cells was accompanied by reduced expression of the co-stimulatory molecules, ICOS and PD-1, and total blockade of the production of inflammatory cytokines such as IFNg and IL-17.
ConclusionOur findings indicate a potential mechanism via which this compound may be effective in inhibiting FcR-driven T cell responses and
ameliorating chronic articular inflammation.
Spleen tyrosine kinase (SYK) is a core signaling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune-receptors including the B cell
receptor (BCR) and Fc receptors (FcRs). The small molecule SYK inhibitor, fostamatinib, has shown evidence of ameliorating inflammation in rheumatoid arthritis (RA) patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level. It has been shown that R406 reduces the response of dendritic cells (DCs) to immune complexes (ICs) and we have previously demonstrated that the area and duration of interaction between T cells and DCs are key
determinants in the outcome of an immune response.
MethodsFluorescence microscopy was combined with CD4 T cells from T cell receptor transgenic OT-II mice to track antigen-specific interactions
between DCs and T cells in vitro.
ResultsWe have found that R406 reduces the DC-T cell contact area and the number of interactions lasting more than 5 minutes during the initial
phase of cellular cross-talk between IC-activated DCs and antigen-specific CD4 T cells. This led to diminished proliferation with 19.20.5% of OT-II CD4 T cells undergoing proliferation (and only a maximum of two rounds) after R406 treatment compared with 79.62.0% in vehicle controls. This reduced proliferative capacity of CD4 T cells was accompanied by reduced expression of the co-stimulatory molecules, ICOS and PD-1, and total blockade of the production of inflammatory cytokines such as IFNg and IL-17.
ConclusionOur findings indicate a potential mechanism via which this compound may be effective in inhibiting FcR-driven T cell responses and
ameliorating chronic articular inflammation.
| Original language | English |
|---|---|
| Article number | 716 |
| Pages (from-to) | S304-S304 |
| Number of pages | 1 |
| Journal | Arthritis and Rheumatism |
| Volume | 65 |
| Issue number | S10 |
| DOIs | |
| Publication status | Published - 1 Oct 2013 |
| Externally published | Yes |
| Event | American College of Rheumatology 2013 Annual Meeting - San Diego, United States Duration: 25 Oct 2013 → 30 Oct 2013 |