Tyrosine kinase inhibitors (TKis) effectively limit autoimmunity in animal models and are under clinical study in RA, MS and psoriasis. Recent studies in NOD mice have demonstrated proof-of-principal for promiscuous PTK blockade, using inhibitors initially developed to inhibit oncogenic pathways in cancer. Our recent work has shown that the selective Syk inhibitor R788 limits diabetes progression in NOD mice. Spleen tyrosine kinase (Syk) is most widely known as the PTK downstream of the B cell antigen receptor (BCR) and the IgG receptor (FcR) in myeloid cells and Syk PTKis have demonstrated clinical activity in RA and ITP. R788-treated NOD mice had decreased autoantibody levels presumably the result of BCR-inhibition and decreased T cell priming likely due to syk inhibition in DCs. A direct effect of Syk inhibtion on T cells was not reported, since syk expression in T cells was not expected. However, aberrant Syk expression may occur in autoimmune T cells. Indeed in our preliminary studies, discussed below, Syk is seen expressed in autoaggressive CD8 T cells infiltrating the skin and in activated murine and human T cells ex vivo.

Targeting of T cell activation via small molecule interference with protein tyrosine kinases is a promising approach to autoimmunity and could be directed at TCR signaling or co-stimulatory pathways. In T1D, these efforts will require determination of which signal transduction targets are specifically expressed in diabetogenic T cells in the islet and pancreatic lymph node. Autoaggressive T cells responding to sustained autoantigen drive may express signal transducing molecules not ordinarily expressed in resting or transiently active normal T cells thus providing attractive therapeutic targets. Our preliminary data shows that the Syk kinase is expressed in persistently activated T cells in vitro and in autoimmune T cells in vivo.