Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The complement system plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Apart from the activation of the early components of the classical complement cascade, C5a levels are elevated in SLE patient plasma and C5a receptor (C5aR)-positive cells are detected in kidneys from lupus nephritis (LN) patients. We compared the expression of C5a and C5aR in samples of LN patients to healthy control samples. Moreover, we investigated the efficacy of blocking C5aR by prophylactic treatment with an anti-C5aR monoclonal antibody (mAb) in the inducible nephrotoxic nephritis (NTN) mouse model, which can be viewed as a mechanistic disease model of kidney damage downstream of immune complex (IC) deposition in the glomeruli leading to glomerulonephritis (GN).
Methods:
C5a was measured in urine samples of 20 LN patients and in 10 healthy controls by ELISA at 3 visits. The expression of C5aR, CD3 and CD68 was investigated by immunohistochemistry in kidney biopsies from 9 LN patients and from 3 non-inflamed controls. GN was induced by transferring nephrotoxic serum containing sheep anti-rat GBM IgG antibodies into C57BL/6 mice pre-immunized with sheep IgG in CFA. Prophylactic administration of 5 or 25 mg/kg anti-C5aR mAb, 25 mg/kg isotype control or PBS was performed 3x weekly (n=12 per group). Sheep IgG specific antibody titers were determined by ELISA and GN development was monitored by proteinuria measurements (Uristix). Pathological changes of the kidney were analysed by periodic acid-Schiff stain. Mouse C5a was measured in renal tissue and in urine samples by ELISA.
Results:
In 17 out of 20 LN patients, C5a was detectable in the urine, but not in any of the healthy controls. In kidney biopsies, C5aR was expressed by infiltrating cells located in T cell (CD3+) and macrophage (CD68+) rich lymphoid aggregates in the tubulointerstitium in 7 out of 9 LN patients. No C5aR expression was observed in normal renal tissue. In the murine NTN model, both doses of anti-C5aR mAb inhibited development of proteinuria and reduced the frequency of glomeruli showing basal membrane (BM) thickening. The prevalence of affected glomeruli correlated with the development of proteinuria. C5a was detected in renal tissue and urine samples upon NTN induction. No changes in C5a or in anti-sheep IgG Ab titers were detected following C5aR blockade, suggesting that anti-C5aR mAb treatment targets effector functions downstream of IC deposition.
Conclusion:
Preventive treatment with anti-C5aR mAb diminishes the development of proteinuria and attenuates glomerular BM thickening. This demonstrates that blockade of C5aR abrogates the development of GN in the NTN mouse model. These data combined with the detection of C5a in LN patient urine and C5aR-positive infiltrating cells in renal samples from LN patients suggest that blocking C5aR with antagonistic mAbs might be a promising future therapy of patients with LN.
Disclosure:
C. Hess,
Novo Nordisk A/S,
3;
D. Tornehave,
Novo Nordisk A/S,
3;
P. H. Kvist,
Novo Nordisk A/S,
3;
Y. Sundström,
None;
L. Berg,
None;
I. Gunnarsson,
None;
S. Jacobsen,
Novo Nordisk A/S,
5;
C. Haase,
Novo Nordisk A/S,
3;
L. Hornum,
Noro Nordisk A/S,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-for-involvement-of-c5a-receptor-in-human-and-murine-lupus-nephritis/