ANTI-CD40 LIGAND ANTIBODY TREATMENT OF SNF1 MICE WITH ESTABLISHED NEPHRITIS - PRESERVATION OF KIDNEY-FUNCTION

Prior studies have demonstrated that treatment of young, prenephritic lupus-prone mice with Ab directed against CD40 ligand (CD40L) prolongs survival and decreases the incidence of severe nephritis, In this rep ort, we show that for (SWR x NZB)F-1 (SNF1) animals with established l upus nephritis, long-term treatment with anti-CD40L beginning at eithe r 5.5 or 7 mo of age prolonged survival and decreased the incidence of severe nephritis, ''Older'' mice were chosen for these studies to mor e closely resemble the clinical presentation of patients with establis hed renal disease, We show that age at the start of treatment, which t ypically correlates with severity of disease, is an important factor w hen determining an efficacious therapeutic protocol since animals that began treatment at 7 mo of age required a more aggressive treatment p rotocol than animals at 5.5 mo of age, Remarkably, several anti-CD40L- treated animals beginning treatment at age 5.5 mo demonstrated a decli ne in proteinuria, as opposed to increasing proteinuria levels seen in hamster IgG (HIg)-treated controls, and histologic examination of kid neys from anti-CD40L-treated mice revealed dramatically diminished inf lammation, sclerosis/fibrosis, and vasculitis, in marked contrast to t he massive inflammation and kidney destruction observed in control ani mals that received hamster IgG, Spleens from anti-CD40L-treated mice a lso exhibited markedly reduced inflammation and fibrosis compared with controls, Together, these results show that treatment of older, nephr itic SNF1 animals with long-term anti-CD40L immunotherapy significantl y prolongs survival, reduces the severity of nephritis, and diminishes associated inflammation, vasculitis, and fibrosis.