Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients

Abstract

The CD40-CD40L system has pleiotropic effects in a variety of cells and biological processes including immune response, thrombosis and atherogenesis. Within the immune system, these molecules representa critical link between its humoral and cellular arms. As a result of these attributes and based on preclinical data in animals, anti-CD40L antibodies were tested in a variety of immunologic diseases including idiopathic thrombocytopenic purpura, psoriasis, Crohn’s disease, systemic lupus erythematosus and transplantation.Phase I/II studies in humans with lupus nephritis demonstrated reduction of anti-double-strandedDNA (anti-dsDNA) antibodies but not of protective antibodies. Reduction of anti-DNA was associated with increased serum complement levels and reduced glomerularinflammation. As a result of thromboticeffects, observed even in patients negative for anti-cardiolipinantibodies, there is a temporary halt on further human studies. The reasons for the prothrombotic effects are not clear at present but may represent effects on platelets and/or the endothelium. In view of the significant immunomodulatory effects of anti-CD40L treatment in patients with lupus nephritis, the increasing realizationof the importance of premature atherosclerosis in lupus and an increasing amount of data supportinga role for the CD40-CD40L interactionsin this process, inhibition of this pathway deserves further exploration in lupus.