Agonistic anti-CD40 promotes early development and increases the incidence of severe thyroid epithelial cell hyperplasia (TEC H/P) in CD4 -/- mice

IFN-gamma -/- NOD. H-2h4 mice develop thyroid epithelial cell hyperplasia (TEC H/ P) characterised by abnormal proliferation of thyrocytes and infiltration of thyroids by CD4+ and CD8+ T cells, macrophages and dendritic cells. CD8+ T cells from mice with severe TEC H/ P transfer similar lesions to SCID recipients, whereas CD4+ T cells transfer mild TEC H/ P. CD4-and CD8-deficient IFN-gamma -/- NOD. H-2h4 mice were generated to determine if CD4+ T cells were required for initial activation of the CD8+ T cells that transfer TEC H/ P. After 6-8 months on NaI water, only 2 of 60 CD8 -/- mice developed severe TEC H/ P, whereas 31 of 101 CD4 -/- mice developed severe TEC H/ P and fibrosis comparable in severity to that of IFN-gamma -/- mice. However, splenocytes from CD4 -/- mice with severe TEC H/ P did not effectively transfer severe TEC H/ P to SCID recipients. When CD4 -/- donors were given agonistic anti-CD40mAb, most developed severe TEC H/ P and their cells transferred severe TEC H/ P to SCID recipients. These results indicate that agonistic anti-CD40 can provide an important signal for activation of autoreactive CD8+ T cells that transfer severe TEC H/ P. Therefore, targeting or blocking CD40 could provide effective therapy for diseases involving hyperplasia and fibrosis mediated by CD8+ T cells.