Residual EAE severity following B cell depletion is due to treatment-resistant plasma cells (THER7P.953)

Abstract

Plasma cells and the autoreactive antibodies they produce are suspected to contribute to the pathogenesis of Multiple Sclerosis, but recent attempts to target these components of humoral immunity have failed. Recently we reported that MEDI551, an anti-CD19 antibody, disrupts development of EAE, the mouse model of MS. Leukocyte infiltration into the spinal cord is significantly reduced as well as short- and long-lived autoreactive CD138+ plasma cells in the spleen and bone marrow. In addition, potentially protective CD1dhiCD5+ regulatory B cells show resistance to depletion, and myelin-specific FoxP3+ regulatory T cells are expanded. Thus, MEDI551 may offer a compelling alternative that reduces pathogenic adaptive immune responses while preserving regulatory mechanisms. The sparing of long-lived plasma cells by anti-CD20 therapies and targeting of this population by MEDI551 prompted us to compare the efficacy of anti-CD19 Ab and anti-CD20 Ab in our EAE model. Our data demonstrated that anti-CD19 depletion is more effective than anti-CD20 depletion to ameliorate EAE. In fact, the frequency of residual antibody-producing cells correlated with residual disease severity in both the anti-CD19 and anti-CD20 treatment groups. No other correlations with residual EAE severity were found. We conclude that CD19+ plasma cells remaining after B cell depletion therapy contribute to residual EAE severity by producing autoreactive antibodies and pro-inflammatory factors.