Depletion of B cells in murine lupus: efficacy and resistance.
In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rheumatoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Fas(lpr) (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.
Ahuja
Anupama
A
Department of Laboratory Medicine, Yale University, New Haven, CT 06510, USA.
Shupe
Jonathan
J
Dunn
Robert
R
Kashgarian
Michael
M
Kehry
Marilyn R
MR
Shlomchik
Mark J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002452:Cell Count; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
C507846:8H9 monoclonal antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies