B cell‐targeted therapy with anti‐CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism
Graves' disease is a B cell‐mediated and T cell‐dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti‐thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen‐presenting/immune‐modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti‐mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A‐subunit (Ad‐TSHR289). We observe that a single injection of 250 µg/mouse anti‐mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR‐specific splenocyte secretion of interferon (IFN)‐γ, anti‐TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time‐point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN‐γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody‐producing cells but also as antigen‐presenting/immune‐modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.