ATTENUATION OF IMMUNE-MEDIATED GLOMERULONEPHRITIS WITH AN ANTI-CD11B MONOCLONAL-ANTIBODY

Nephrotoxic nephritis (NTN), a model of autoimmune glomerulonephritis, is characterized by glomerular inflammation, which results in both pr oteinuria and an increase in eicosanoid production. In light of the ab ility of CD18 integrins to participate in leukocyte adherence (and the reby migration), we examined-the role of the integrin CD11b/CD18 in NT N using OX42, a monoclonal antibody directed against rat CD11b. Admini stration of OX42 30 min before induction of NTN decreased proteinuria (by 50%) but did not affect the number of leukocytes found in the glom erulus or the accompanying increase in glomerular eicosanoid productio n. Administration of OX42 16 h before disease induction led to a more substantial decrease in proteinuria (80%) and, in contrast to 30 min p retreatment, decreased the number of neutrophils found in the glomerul us and the accompanying increase in glomerular eicosanoid production ( both by 50%). OX42 pretreatment had no effect on the number of macroph ages found in glomeruli. Circulating leukocytes from animals treated w ith OX42 in vivo showed saturating surface levels of antibody by fluor escence-activated cell sorting (FACS) analysis and normal upregulation of CD11b by pharmacological activation. Sixteen hours after in vivo i njection of OX42, 50% more peripheral leukocytes were labeled relative to control leukocytes labeled with OX42 ex vivo. Glomerular leukocyte s in NTN exhibited upregulated expression of CD11b relative to periphe ral leukocytes. These data show that CD11b/CD18 may participate in the acute expression of glomerular damage in NTN in a fashion not wholly dependent on blocking neutrophil migration into glomeruli. Blockade of surface receptors (as opposed to inhibition of upregulation) is suffi cient to obtain this effect.