Immunology Graduate Program | University of California, San Francisco

Dr. Wofsy’s research group conducts clinical trials of novel biologic therapies for people with autoimmune diseases. At present, these trials focus on the treatment of systemic lupus erythematosus wih agents that inhibit B-cell and/or T cell activation. Agents under investigation include anti-CD20, TACI-Ig, and CTLA4Ig.

For many years, our laboratory focused on the cellular and molecular mechanisms that lead to autoimmune disease in murine models for systemic lupus erythematosus (SLE). The principal strategy of this work was to use monoclonal antilymphocyte antibodies or genetically-engineered fusion proteins to inhibit the function of selected lymphocyte subsets in mice that spontaneously develop an illness that closely resembles SLE in people. By so doing, we sought to achieve two goals. First, by inhibiting selected cells in lupus-prone mice, we sought to determine the role of these cells in the pathogenesis of autoimmune disease. Second, by identifying the cellular and molecular interactions that promote SLE, we sought to develop new approaches to treatment.

We have been particularly interested in new therapeutic strategies that focus on molecules that are expressed preferentially on the surface of activated lymphocytes or antigen-presenting cells (APC). By inhibiting primarily activated cells, these therapies are designed to block pathologic immune responses without damaging the entire lymphocyte repertoire. One example of such a strategy involves the B7 family of molecules on APC. These molecules play a pivotal role in the generation of T-cell help. Specifically, the interaction of B7 molecules on APC with their ligand (designated CD28) on T cells provides an important signal for T-cell activation. We first showed that selective inhibition of the B7-CD28 interaction retards autoimmunity in a mouse model for SLE (Science 265:1225-1227,1994). We subsequently showed that this beneficial effect could be enhanced substantially in two ways: (i) by combining blockade of B7-CD28 with blockade of other receptor-ligand pairs (CD40-CD40L) on the surface of T cells and APC (J Immunol 159:3104-3108,1997; and (ii) by combining blockade of B7-CD28 with cyclophosphamide therapy (J Immunol 166:2913-2916, 2001), the current gold standard for the treatment of lupus nephritis in people. In each case, combination therapy provided a prolonged benefit without sustained generalized immune suppression.

Based on our findings in murine models for SLE, we decided several years ago to make a transition toward translational research designed to test new therapeutic strategies in people with SLE. We have had considerable success in this area. First, we performed Phase I and Phase II trials of anti-CD40L in people with SLE. This work constituted the first controlled trial of a novel biologic agent in SLE (Arthritis Rheum 46:3251-358, 2002). Since that time, we have initiated trials of CTLA4Ig, TACI-Ig, and mycophenolate mofetil in SLE. All of these studies are currently in progress.