Depletion of B cells in murine lupus: efficacy and resistance

A Ahuja, J Shupe, R Dunn, M Kashgarian… - The Journal of …, 2007 - journals.aai.org
A Ahuja, J Shupe, R Dunn, M Kashgarian, MR Kehry, MJ Shlomchik
The Journal of Immunology, 2007journals.aai.org
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 rhematoid 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 …
Abstract
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 rhematoid 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 nonautoimmune-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.
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