Therapeutic targeting of Syk in autoimmune diabetes.
In APCs, the protein tyrosine kinase Syk is required for signaling of several immunoreceptors, including the BCR and FcR. We show that conditional ablation of the syk gene in dendritic cells (DCs) abrogates FcgammaR-mediated cross priming of diabetogenic T cells in RIP-mOVA mice, a situation phenocopied in wild-type RIP-mOVA mice treated with the selective Syk inhibitor R788. In addition to blocking FcgammaR-mediated events, R788 also blocked BCR-mediated Ag presentation, thus broadly interrupting the humoral contributions to T cell-driven autoimmunity. Indeed, oral administration of R788 significantly delayed spontaneous diabetes onset in NOD mice and successfully delayed progression of early-established diabetes even when treatment was initiated after the development of glucose intolerance. At the DC level, R788 treatment was associated with reduced insulin-specific CD8 priming and decreased DC numbers. At the B cell level, R788 reduced total B cell numbers and total Ig concentrations. Interestingly, R788 increased the number of IL-10-producing B cells, thus inducing a tolerogenic B cell population with immunomodulatory activity. Taken together, we show by genetic and pharmacologic approaches that Syk in APCs is an attractive target in T cell-mediated autoimmune diseases such as type 1 diabetes.
Colonna
Lucrezia
L
Department of Medicine, Columbia University Medical Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Catalano
Geoffrey
G
Chew
Claude
C
D'Agati
Vivette
V
Thomas
James W
JW
Wong
F Susan
FS
Schmitz
Jochen
J
Masuda
Esteban S
ES
Reizis
Boris
B
Tarakhovsky
Alexander
A
Clynes
Raphael
R
D000631:Aminopyridines; D000818:Animals; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D007074:Immunoglobulin G / Q000502:physiology; D007075:Immunoglobulin M / Q000502:physiology; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009025:Morpholines; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010078:Oxazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000502:physiology; D000072377:Syk Kinase
D000631:Aminopyridines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib