Blocking VLA-4 prevents progression of experimental crescentic glomerulonephritis.
OBJECTIVE
Integrins are adhesion molecules of fundamental importance to the recruitment of leucocytes in inflammation. The alpha4beta1 integrin (VLA-4) is a leucocyte ligand for endothelial vascular cell adhesion molecule-1 (VCAM-1), fibronectin and osteopontin. We addressed the role of VLA-4 in mediating progressive renal injury in vivo using a blocking monoclonal antibody (mAb) in a rat model of crescentic glomerulonephritis.


METHODS
WKY rats with nephrotoxic nephritis were given anti-VLA-4 or control mAb at 2.5 mg/kg by i.p. injection on alternate days. In separate experiments, antibodies were given from days 5-13, from days 13-21 or from days 14-28.


RESULTS
Early treatment with anti-VLA-4 mAb from days 5-13 showed a significant effect on renal function, with a reduction in albuminuria (p < 0.01) and a higher creatinine clearance (p < 0.05). Delayed treatment from days 13-21 also showed a reduction in albuminuria (p < 0.05) and serum creatinine (p < 0.05). However, there was no significant effect on glomerular or interstitial scarring in these two experiments. In the late treatment study, in which anti-VLA-4 mAb was administered from days 14-28, serum creatinine was reduced (p < 0.05), creatinine clearance was improved (p < 0.05), and renal survival was significantly prolonged (p < 0.05). Interstitial scarring was significantly less in treated rats (p < 0.05). Glomerular macrophage and CD8+ cell counts were higher in anti-VLA-4 mAb treated rats (p < 0.05), possibly reflecting greater glomerular scarring in control animals.


CONCLUSIONS
Leucocyte VLA-4 mediates pro-inflammatory and pro-fibrotic effects within the kidney, independent of any role in recruitment of leucocytes into the kidney. Blocking VLA-4 is a promising therapeutic approach in human glomerulonephritis.
Khan
Sarah B
SB
Renal Section, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. s.khan@imperial.ac.uk
Allen
Andrew R
AR
Bhangal
Gurjeet
G
Smith
Jennifer
J
Lobb
Roy R
RR
Cook
H Terence
HT
Pusey
Charles D
CD
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000473:pathology / Q000517:prevention & control*; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D002921:Cicatrix / Q000517:prevention & control; D003404:Creatinine / Q000097:blood / Q000378:metabolism / Q000652:urine; D004334:Drug Administration Schedule; D007106:Immune Sera / Q000009:adverse effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D011817:Rabbits; D051381:Rats; D011921:Rats, Inbred WKY
D000911:Antibodies, Monoclonal; D007106:Immune Sera; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D003404:Creatinine