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*
Department of Immunology, Biogen Inc., Cambridge, MA 02142;
Departments of Medicine, Microbiology-Immunology, and Multipurpose Arthritis Center, Northwestern University Medical School, Chicago, IL 60611
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 report, we show that for (SWR x NZB)F1 (SNF1) animals with established lupus nephritis, long-term treatment with anti-CD40L beginning at either 5.5 or 7 mo of age prolonged survival and decreased the incidence of severe nephritis. "Older" mice were chosen for these studies to more closely resemble the clinical presentation of patients with established renal disease. We show that age at the start of treatment, which typically correlates with severity of disease, is an important factor when determining an efficacious therapeutic protocol since animals that began treatment at 7 mo of age required a more aggressive treatment protocol than animals at 5.5 mo of age. Remarkably, several anti-CD40L-treated animals beginning treatment at age 5.5 mo demonstrated a decline in proteinuria, as opposed to increasing proteinuria levels seen in hamster IgG (HIg)-treated controls, and histologic examination of kidneys from anti-CD40L-treated mice revealed dramatically diminished inflammation, sclerosis/fibrosis, and vasculitis, in marked contrast to the massive inflammation and kidney destruction observed in control animals that received hamster IgG. Spleens from anti-CD40L-treated mice also exhibited markedly reduced inflammation and fibrosis compared with controls. Together, these results show that treatment of older, nephritic SNF1 animals with long-term anti-CD40L immunotherapy significantly prolongs survival, reduces the severity of nephritis, and diminishes associated inflammation, vasculitis, and fibrosis.
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