Therapeutic targeting of Syk in autoimmune diabetes.

Abstract

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.

• Authors: Lucrezia Colonna, Geoffrey Catalano, Claude Chew, Vivette D'Agati, James W Thomas, F Susan Wong, Jochen Schmitz, Esteban S Masuda, Boris Reizis, Alexander Tarakhovsky, Raphael Clynes
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 3 Pg. 1532-43 (Aug 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20601600 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Immunoglobulin G
• Immunoglobulin M
• Insulin
• Intracellular Signaling Peptides and Proteins
• Morpholines
• Oxazines
• Pyridines
• Pyrimidines
• Receptors, Antigen, B-Cell
• Receptors, IgG
• Ovalbumin
• Protein-Tyrosine Kinases
• Syk Kinase
• Syk protein, mouse
• fostamatinib

Topics

• Aminopyridines
• Animals
• Cross-Priming (genetics, immunology)
• Dendritic Cells (immunology, metabolism, pathology)
• Diabetes Mellitus, Type 1 (enzymology, immunology, therapy)
• Female
• Gene Targeting (methods)
• Immunoglobulin G (physiology)
• Immunoglobulin M (physiology)
• Insulin (immunology, metabolism)
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Mice, Transgenic
• Morpholines
• Ovalbumin (genetics, immunology)
• Oxazines (therapeutic use)
• Protein-Tyrosine Kinases (deficiency, genetics, physiology)
• Pyridines (therapeutic use)
• Pyrimidines
• Receptors, Antigen, B-Cell (antagonists & inhibitors, physiology)
• Receptors, IgG (antagonists & inhibitors, physiology)
• Syk Kinase