Pre-clinical Evaluation of Syk Inhibitors in Type I Diabetes

Type I Diabetes (T1D) is caused by autoimmune attack of islets by inflammation, with immune cells called T cells recognized as the primary cause of destruction. Yet, a critical role for a second group of immune cells called B cells is evident by the lack of disease in mice lacking B cells. The notion that B cells contribute to T cell mediated autoimmunity, including T1D, has gathered recent support from promising clinical studies in rheumatoid arthritis patients treated with Rituximab. This concept is currently under clinical investigation in T1D, including by our collaborator Kevan Herold who is a lead investigator. This approach, however, incompletely blocks B cell contributions to autoimmunity since Rituximab does not interfere with the pathogenic contributions of autoimmune B cell products, anti-islet antibodies. We propose to more broadly target the contributions of B cells in pre-clinical models of T1D using R406/788, a selective inhibitor of the syk protein tyrosine kinase. Since syk activity is required for signaling of both B cell receptors and the receptors for antibodies (called Fc receptors), syk inhibition provides the substantial benefit of complete abrogation of autoantibody, function. both as mediated by B cells and by Fc receptor-bearing cells. Initial studies have demonstrated that treatment of NOD mice treated with oral syk inhibitors beginning at 6 weeks of age prevents T1D development. Should our proposed pre-clinical models continue to demonstrate efficacy, we would be well-positioned for rapid clinical evaluation in T1D, since the early clinical experience with R406/788 and other oral syk inhibitors have demonstrated an acceptable toxicity profile to date. We propose the following pre-clinical studies in anticipation of clinical development.Aim 1A) Does pharmacologic blockade of syk in the pre-diabetic window prevent diabetes througout adulthood in NOD mice? Aim 1B) Does pharmacologic blockade of syk in adult mice reverse early-established diabetes in NOD?Aims 2 and 3) What are the physiologically relevant protective mechanism(s) underlying T1D prevention by syk blockade?