Pre-clinical evaluation of syk inhibitors in T1D

The syk kinase is required for immune activation by the antibody-limb of the immune system. As such it is an inviting therapeutic target in autoimmunity, including type I diabetes. The role of the antibody or humoral limb of the immune response was recently found to critically contribute in mouse models of diabetes and its importance as a therapeutic target is currently under clinical investigation using drugs which kill (most but not all) antibody-producing cells (B cells). We hypothesize that a more effective approach would be inhibit the activation of B cells with drugs that block the key signaling molecule (syk) inside all B cells. In addition to allowing B cell survival, this approach his would have the added advantage of blocking other key activation steps mediated by secreted antibodies which we have identifies as potentially causal in diabetes development. This second pathway occurs in dendritic cells which are responsible for displaying self-antigen to T cells. Secreted autoantibodies have the capacity to bind self antigens, forming immune complexes which contain islet antigens. These immune complexes can activate dendritic cells-empowering them to display these antigens and stimulate autoimmune T cells. Blocking syk in dendritic cells would block this second antibody-mediated pathway, thus blocking two aspects of antibody-mediated activation both in B cells and in dendritic cells.

We will perform mechanistic studies to prevent T cell activation using syk antagonists in a model system we have developed to investigate antibody contributions to autoimmune diabetes using syk antagonists. Importantly, we will also treat NOC mice with syk antagonists to block the development of spontaneous diabetes.