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

Andrew M Platt, Robert A Benson, Ross McQueenie, John P Butcher, Martin Braddock, James M Brewer, Iain B McInnes, Paul Garside

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level.

METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells.

RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17.

CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.

Original languageEnglish
Pages (from-to)169-77
Number of pages9
JournalRheumatology
Volume54
Issue number1
DOIs
Publication statusPublished - Jan 2015

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Dendritic Cells
T-Lymphocytes
Antigen-Antibody Complex
Inducible T-Cell Co-Stimulator Protein
Antigens
CD4 Antigens
Interleukin-17
Fc Receptors
Fluorescence Microscopy
Syk Kinase
fostamatinib
Immunization
B-Lymphocytes
Cell Proliferation
Cytokines
Inflammation
Proteins
In Vitro Techniques

Keywords

  • Administration, Oral
  • Animals
  • Antigen-Antibody Complex
  • CD4-Positive T-Lymphocytes
  • Cell Communication
  • Cell Proliferation
  • Cells, Cultured
  • Chemokines
  • Cytokines
  • Dendritic Cells
  • Enzyme Inhibitors
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Models, Animal
  • Oxazines
  • Protein-Tyrosine Kinases
  • Pyridines

Cite this

Platt, A. M., Benson, R. A., McQueenie, R., Butcher, J. P., Braddock, M., Brewer, J. M., ... Garside, P. (2015). The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells. Rheumatology, 54(1), 169-77. https://doi.org/10.1093/rheumatology/keu273
Platt, Andrew M ; Benson, Robert A ; McQueenie, Ross ; Butcher, John P ; Braddock, Martin ; Brewer, James M ; McInnes, Iain B ; Garside, Paul. / The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells. In: Rheumatology. 2015 ; Vol. 54, No. 1. pp. 169-77.
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abstract = "OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level.METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells.RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17.CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.",
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Platt, AM, Benson, RA, McQueenie, R, Butcher, JP, Braddock, M, Brewer, JM, McInnes, IB & Garside, P 2015, 'The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells' Rheumatology, vol. 54, no. 1, pp. 169-77. https://doi.org/10.1093/rheumatology/keu273

The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells. / Platt, Andrew M; Benson, Robert A; McQueenie, Ross; Butcher, John P; Braddock, Martin; Brewer, James M; McInnes, Iain B; Garside, Paul.

In: Rheumatology, Vol. 54, No. 1, 01.2015, p. 169-77.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells

AU - Platt, Andrew M

AU - Benson, Robert A

AU - McQueenie, Ross

AU - Butcher, John P

AU - Braddock, Martin

AU - Brewer, James M

AU - McInnes, Iain B

AU - Garside, Paul

N1 - © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015/1

Y1 - 2015/1

N2 - OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level.METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells.RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17.CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.

AB - OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level.METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells.RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17.CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.

KW - Administration, Oral

KW - Animals

KW - Antigen-Antibody Complex

KW - CD4-Positive T-Lymphocytes

KW - Cell Communication

KW - Cell Proliferation

KW - Cells, Cultured

KW - Chemokines

KW - Cytokines

KW - Dendritic Cells

KW - Enzyme Inhibitors

KW - In Vitro Techniques

KW - Intracellular Signaling Peptides and Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Models, Animal

KW - Oxazines

KW - Protein-Tyrosine Kinases

KW - Pyridines

U2 - 10.1093/rheumatology/keu273

DO - 10.1093/rheumatology/keu273

M3 - Article

VL - 54

SP - 169

EP - 177

JO - Rheumatology

JF - Rheumatology

SN - 1462-0324

IS - 1

ER -