| Immunomodulation of self-antigen presentation by professional antigen presenting cells might hold therapeutic promise in the treatment of autoimmune diseases. The spleen tyrosine kinase or Syk represents the proximal protein tyrosine kinase required for the transmission of activating signaling events by both the B cell and Fcgamma immunoreceptors. Targeting Syk offers the potential to block early activating signals following the uptake of self-antigen by the B cell receptor, and of self-antigen-containing immune complexes by Fcgamma receptors, therefore inhibiting self-antigen presentation. The small molecule, ATP-binding, multikinase inhibitor R406/R788, which demonstrated considerable selectivity for Syk, is shown here to inhibit B cell and FcgammaR-mediated cellular activation and antigen presentation by both B cells and dendritic cells in vitro. In vivo treatment with R406/R788 of NOD mice, the best model for human autoimmune type 1 diabetes, prevents disease progression in pre-diabetic mice, as well as in early diabetic animals with impaired glucose tolerance. Syk blockade is shown here to have a minor inhibitory effect on the humoral response, without major alterations on B cell development. Total IgG as well as islet antigen specific IgG were mildly reduced in R406/R788-treated mice. Following the transfer of diabetogenic splenocytes into NOD/SCID recipients, protection was afforded when donor mice were treated with R406/R788 prior to diabetes development. On the other hand, treatment of NOD/SCID recipients failed to protect, consistent with blockade of the priming rather than the effector phase of the autoimmune response. In line with these observations, R406/R788 inhibited the expansion of insulin-specific autoreactive CD8 T cells in pre-diabetic mice. In addition to blocking T cell priming, R406/788 treatment promoted the accumulation of IL-10-producing regulatory B cells in the spleen and peritoneal cavity of treated mice.;These studies provide evidence for the therapeutic potential of Syk targeting in inhibiting self-antigen presentation and promoting tolerogenic mechanisms in type I diabetes and in other T cell mediated autoimmune diseases. |
