The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis.
BACKGROUND
Blockade of CD40-CD40 ligand (CD154) interactions protects against renal injury in adriamycin nephropathy (AN) in immunocompetent mice. To investigate whether this protection relied on adaptive or cognate immunity, we tested the effect of CD40-CD154 blockade in severe combined immunodeficient (SCID) mice.


METHODS
SCID mice were divided into three groups: normal, AN + hamster IgG (ADR+IgG group) and AN + anti-CD154 antibody (MR1) (ADR+MR1 group). AN was induced by tail vein injection of 5.2 mg/kg of adriamycin (ADR). Hamster IgG (control Ab) or MR1 was administered intraperitoneally on days 5, 7, 9 and 11 after ADR injection. Histological and functional data were collected 4 weeks after ADR injection. In vitro experiments tested the effect of soluble and cell-bound CD154 co-cultured with CD40-expressing cells [macrophages, mesangial cells and renal tubular epithelial cells (RTEC)].


RESULTS
All experimental animals developed nephropathy. Compared to the ADR+IgG group, ADR+MR1 animals had significantly less histological injury (glomerulosclerosis and tubular atrophy) and functional injury (creatinine clearance). Kidneys of ADR+MR1 animals had significantly less macrophage infiltration than those of ADR+IgG animals. Interestingly, expression of CD40 and CD41 (a platelet-specific marker) was significantly less in ADR+MR1 animals compared to ADR+IgG animals. In vitro, CD154 blockade significantly attenuated upregulation of CCL2 gene expression by RTEC stimulated by activated macrophage-conditioned medium. In contrast, platelet-induced upregulation of macrophage and mesangial cell proinflammatory cytokine gene expression were not CD154-dependent.


CONCLUSIONS
CD40-CD154 blockade has a significant innate renoprotective effect in ADR nephrosis. This is potentially due to inhibition of macrophage-derived soluble CD154.
Lee
Vincent W S
VW
Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia. vincent_lee@wmi.usyd.edu.au
Qin
Xiaohong
X
Wang
Yiping
Y
Zheng
Guoping
G
Wang
Ya
Y
Wang
Ying
Y
Ince
Jon
J
Tan
Thian K
TK
Kairaitis
Lukas K
LK
Alexander
Stephen I
SI
Harris
David C H
DC
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000502:physiology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000502:physiology*; D018932:Chemokine CCL2 / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009401:Nephrosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D023201:CD40 Ligand; D004317:Doxorubicin