Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients.
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 represent a 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-stranded DNA (anti-dsDNA) antibodies but not of protective antibodies. Reduction of anti-DNA was associated with increased serum complement levels and reduced glomerular inflammation. As a result of thrombotic effects, observed even in patients negative for anti-cardiolipin antibodies, 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 realization of the importance of premature atherosclerosis in lupus and an increasing amount of data supporting a role for the CD40-CD40L interactions in this process, inhibition of this pathway deserves further exploration in lupus.
Sidiropoulos
P I
PI
Division of Rheumatology, Clinical Immunology and Allergy, University of Crete, Medical School, Heraklion, Greece.
Boumpas
D T
DT
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000628:therapy*
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand