Mechanisms of T cell-induced glomerular injury in anti-glomerular basement membrane (GBM) glomerulonephritis in rats.
The effector mechanisms of T cell-dependent acute glomerular injury were studied in autologous phase anti-GBM glomerulonephritis (GN) in rats. Acute proliferative GN was induced in sensitized rats by a subnephritogenic dose of sheep anti-rat GBM antibody. Injury was manifested by proteinuria and glomerular leucocyte infiltration composed predominantly of macrophages but also CD4+ and CD8+ T cells. T cell depletion, using an anti-CD5 MoAb, demonstrated that glomerular leucocyte infiltration and proteinuria were T cell-dependent. Inhibition of T helper cell function using an anti-CD4 MoAb prevented proteinuria and glomerular macrophage and CD4+ T cell influx, but not accumulation of CD8+ T cells. Depletion of CD8+ T cells also prevented proteinuria and the influx of macrophages and CD8+ T cells, but not accumulation of CD4+ T cells. Macrophage depletion, using micro-encapsulated clodronate, prevented proteinuria and glomerular macrophage infiltration, but not the accumulation of CD4+ or CD8+ T cells, indicating that macrophages are the common cellular effectors for both CD4 and CD8 T cell-dependent injury. Evidence for cytotoxic mechanisms of injury (increased numbers of apoptotic cells or accumulation of natural killer (NK) cells in glomeruli) could not be demonstrated. These data suggest that acute glomerular injury in anti-GBM GN is the result of macrophage recruitment, which is dependent on both CD4 and CD8 T cells, and that direct T cell-mediated injury (cellular cytotoxicity) is not involved.
Huang
X R
XR
Monash University Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Tipping
P G
PG
Apostolopoulos
J
J
Oettinger
C
C
D'Souza
M
M
Milton
G
G
Holdsworth
S R
SR
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004002:Clodronic Acid / Q000494:pharmacology; D003165:Complement System Proteins / Q000032:analysis / Q000276:immunology; D004247:DNA / Q000032:analysis; D005921:Glomerulonephritis / Q000276:immunology*; D007136:Immunoglobulins / Q000032:analysis / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D011507:Proteinuria / Q000175:diagnosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology*
D019138:Antibodies, Blocking; D015704:CD4 Antigens; D007136:Immunoglobulins; D004002:Clodronic Acid; D003165:Complement System Proteins; D004247:DNA