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Objective  The mechanism of action of anti‐B cell therapy in multiple sclerosis ( MS ) is not fully understood. Here, we compared the effect of anti‐ CD 20 therapy on microglial activation in two distinct focal rat models of  MS .    Methods  The effect of anti‐CD20 therapy on lesion formation and extralesional microglial activation was evaluated in the  fDTH ‐ EAE  (experimental allergic encephalomyelitis) model, which is a focal demyelinating type‐IV delayed‐type hypersensitivity lesion. For comparison, effects were also assessed in the focal humoral  MOG  model induced by intracerebral injection of cytokine in myelin oligodendrocyte glycoprotein immunized rats. Microglial activation was assessed  in situ  and  in vivo  using the  TSPO SPECT  ligand [ 125 I]DPA‐713, and by immunostaining for  MHC II. The effect of treatment on demyelination and lymphocyte recruitment to the brain were evaluated.    Results  Anti‐CD20 therapy reduced microglial activation, and lesion formation in the humoral model, but it was most effective in the antibody‐independent  fDTH ‐ EAE . Immunohistochemistry for  MHC II also demonstrated a reduced volume of microglial activation in the brains of anti‐CD20‐treated  fDTH ‐ EAE  animals, which was accompanied by a reduction in T‐cell recruitment and demyelination. The effect anti‐CD20 therapy in the latter model was similarly strong as compared to the T‐cell targeting  MS  compound FTY720.    Interpretation  The suppression of lesion development by anti‐ CD 20 treatment in an antibody‐independent model suggests that B‐cells play an important role in lesion development, independent of auto‐antibody production. Thus,  CD 20‐positive B‐cell depletion has the potential to be effective in a wider population of individuals with  MS  than might have been predicted from our knowledge of the underlying histopathology.

Anti‐CD20 inhibits T cell‐mediated pathology and microgliosis in the rat brain