Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity, autoantibody production, and end organ damage. In certain patients, there is a clear association between anti-dsDNA antibodies and glomerulonephritis. Since renal insufficiency remains the most serious and life threatening complication of SLE, the ability to specifically dampen these antibody responses, without altering normal B cell responses to foreign antigens, would be of significant benefit to these patients. Recently, the La Jolla Pharmaceutical Company developed a B cell toleragen with specificity for anti-dsDNA-producing B lymphocytes. In vitro and in vivo experiments with normal and autoimmune prone mice indicate that this reagent can specifically and significantly diminish DNA antibody production. Based on these and other findings, this reagent is now being used in a phase Il trial in patients with stable SLE whose sera contain anti-dsDNA antibodies. Since our institution is involved in this clinical trial, we have had the opportunity to evaluate the consequences of administration of the toleragen in these patients. Preliminary studies indicate that this reagent has profound effects on the B cell VH gene repertoire, that include the diminution of the diversity of circulating B cell clones and the expansion of a restricted set of clones. We would like to expand these studies to help to elucidate the mechanisms of action of this toleragen. Specifically, we propose to analyze the circulating B cell repertoire in SLE patients, before and after receiving LJP 394 immunotherapy. This will involve molecular analyses of VH CDR3 length and sequence, cellular analyses of antigen binding and antibody production, and serologic analyses of idiotype expression. We also will determine whether tolerance induction involves anergy, deletion, or alterations in circulating B cell subsets and/or cellular trafficking. Since a therapeutic approach that would specifically abrogate pathogenic autoantibodies, without altering responses to appropriate antigenic stimuli, would be a major advance, these studies may be of value for this compound and other toleragens that may become available in the future.
