Autoimmune diseases such as Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Multiple Sclerosis (MS), are caused by immune system attacking the patient’s own organs. In patients with these diseases, immune cells including killer T cells, helper T cells, and antibody producing B cells enter the organs and cause their destruction. A promising strategy to treat autoimmune diseases is to block the movement of immune cells that is required to enter normal tissue prior to destruction. Our preliminary studies have suggested that a key molecule called DOCK2 is responsible for mediating immune cell infiltration into tissues. In this proposal, we will test whether DOCK2 is a suitable therapeutic target to treat autoimmune diseases, including T1D, SLE, and MS. We will use mouse models of these diseases to test if small molecule inhibitors of DOCK2 can block infiltration of immune cells into tissues, thereby preventing and/or delaying autoimmunity. We will also analyze publicly available patient datasets to evaluate if this pathway is active in tissues affected by the autoimmune diseases. If successful, our research will establish DOCK2 as a target for developing novel therapies to treat multiple autoimmune diseases.

T cells are key mediators of immune infiltration and destruction in multiple autoimmune disorders including T1D, SLE, and MS. Autoreactive T cells recognizing self-antigens are primed in lymph nodes (LNs) and infiltrate tissues, where they cause destruction through direct cytotoxicity and secretion of inflammatory cytokines. T cell engagement with APCs in draining Lymph Nodes (dLNs) programs specific effector functions and regulates chemotaxis by inducing/controlling the expression of chemokine receptors and integrins. Upon activation, T cells sense cues from tissues including chemokines that drive T cell movement between LNs and inflamed tissues. Elevated chemokine levels characterize the inflamed tissues in T1D, SLE, and MS. A key player in chemokine-mediated T cell motility is DOCK2 (Dedicator of cytokinesis 2), a GTPGDP exchange factor, that activated Rac1, subsequently mediating T cell movement and immune synapse formation. Our preliminary studies in mouse models of T1D and preliminary re-analyses of mouse and patient datasets in SLE and MS suggest that DOCK2 pathway is upregulated in tissue-infiltrating T cells and other immune cells. We also showed that two small molecule inhibitors of DOCK2 (DOCKi) block T cell chemotaxis in vitro. Based on these data, we hypothesize that DOCK2-mediated tissue infiltration is a mechanism common to T1D, SLE, and MS, and can be therapeutically targeted in mouse models and humans. We will test this hypothesis by: A) Testing if DOCK2 inhibition delays or prevents clinical features of autoimmunity in mouse models; B) Evaluating the impact of DOCK2 inhibition on immune infiltrates in affected tissues of treated mice; and C) Assessing the evidence of DOCK2-mediated immune cell migration being active in disease-affected tissues in patients suffering from T1D, SLE, and MS, by analyzing publicly available datasets. We anticipate that DOCKi treatment of mouse models of autoimmunity will lead to diminished immune infiltration into affected tissues, thereby delaying disease progression. If successful, our research will establish DOCK2 inhibition as a therapeutic strategy for T1D, SLE, and MS.