Our main objective is to study the basic immunologic mechanisms underlying the therapeutic effects of a humanized anti-CD40 ligand antibody (anti-CD40L, BG9588) administered into patients with active lupus nephritis. A total of about 120 patients in 28 centers are participating in this randomized, double- blind, controlled, multiple-dose study of anti-CD40L (BG9588) sponsored by Biogen Inc. Molecular interactions between CD40L and CD40 provides essential costimulatory signals for humoral and cellular immune responses. Most remarkably, CD40L is hyperexpressed by lupus T and B cells for abnormally prolonged periods -- thus sustaining the production of pathogenic autoantibodies. Moreover, a brief therapy of three- injections of anti-CD40L in one week into lupus mice prevents the development of nephritis for more than a year. The mechanism of such a long-term benefit, which is equivalent to 3-4 decades in humans, is unknown. This clinical trial provides an unprecedented opportunity to study the effects of anti-CD40L on the human immune system in vivo, particularly on the cells participating in the chronic ongoing autoimmune response in lupus patients. We will study the status of autoimmune T and B cells that are involved in the production of pathogenic anti-nuclear autoantibodies, before, during and after therapy to answer the following questions: I. Are autoimmune T cells, particularly the ones that respond to nucleosomal peptides and drive the production of pathogenic anti-DNA autoantibodies, deleted or anergized in the anti-CD40L treated patients? II. Are autoimmmune B cells of lupus that make pathogenic autoantibodies and are nucleosome-specific, deleted or anergized by anti-CD40L therapy? III. Are regulatory T cells that could suppress autoantibody production, generated by anti-CD40L therapy? We expect to know more about the workings of the normal and lupus immune systems in humans from these studies.
| Yi, Y; McNerney, M; Datta, S K (2000) Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol 165:6627-34 |
| Lu, L; Kaliyaperumal, A; Boumpas, D T et al. (1999) Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J Clin Invest 104:345-55 |
