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 proteinuria and an increase in eicosanoid production. In light of the ability of CD18 integrins to participate in leukocyte adherence (and thereby migration), we examined the role of the integrin CD11b/CD18 in NTN using OX42, a monoclonal antibody directed against rat CD11b. Administration of OX42 30 min before induction of NTN decreased proteinuria (by 50%) but did not affect the number of leukocytes found in the glomerulus or the accompanying increase in glomerular eicosanoid production. Administration of OX42 16 h before disease induction led to a more substantial decrease in proteinuria (80%) and, in contrast to 30 min pretreatment, decreased the number of neutrophils found in the glomerulus and the accompanying increase in glomerular eicosanoid production (both by 50%). OX42 pretreatment had no effect on the number of macrophages found in glomeruli. Circulating leukocytes from animals treated with OX42 in vivo showed saturating surface levels of antibody by fluorescence-activated cell sorting (FACS) analysis and normal upregulation of CD11b by pharmacological activation. Sixteen hours after in vivo injection of OX42, 50% more peripheral leukocytes were labeled relative to control leukocytes labeled with OX42 ex vivo. Glomerular leukocytes in NTN exhibited upregulated expression of CD11b relative to peripheral 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 sufficient to obtain this effect.
Wu
X
X
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Pippin
J
J
Lefkowith
J B
JB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D018845:CD11 Antigens; D002465:Cell Movement / Q000502:physiology; D015777:Eicosanoids / Q000378:metabolism; D005434:Flow Cytometry; D005453:Fluorescence; D005921:Glomerulonephritis / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011507:Proteinuria / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D015777:Eicosanoids