Passive immunization against tumour necrosis factor-alpha (TNF-α) and IL-lβ protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats

Author:

KARKAR A M1,KOSHINO Y1,CASHMAN S J1,DASH A C1,BONNEFOY J2,MEAGER A3,REES A J1

Affiliation:

1. Renal Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK

2. Glaxo Institute for Molecular Biology, Plan-les-Ouates, Geneva, Switzerland

3. National Institute for Biological Standards and Control, Potters Bar, Herts, UK

Abstract

SUMMARY Glomerular injury caused by injection of heterologous anti-glomerular basement membrane antibodies (anti-GBM Ab) is increased in rats pretreated with small doses of bacterial lipopolysaccharide (LPS). We have investigated the involvement of tumour necrosis factor-alpha (TNF-α), IL-lα and IL-1 β in this phenomenon by passive immunization against these cytokines. Anti-TNF-α or anti-IL-1β antibodies given 1·5 h before the induction of nephritis significantly decreased injury in this model, whether assessed by the magnitude of albuminuria, the prevalence of glomerular capillary thrombi or the intensity of glomerular neutrophil infiltrate. Albuminuria in anti-GBM Ab alone was 11 ± 3, LPS/anti-GBM Ab 87±22, and anti-TNF-α antibodies/LPS/anti-GBM Ab 21 ±6 mg/24 h (mean ± s.e.) P< 0·05. Passive immunization with antibodies to IL-1 β had a similar effect (anti-GBM Ab, 0·6±01, LPS/anti-GBM Ab, 92±19, anti-IL-1β antibodies/LPS/anti-GBM Ab 39 ± 8 mg/24 h, P<0·05). The prevalence of glomerular capillary thrombi was also reduced significantly by these treatments; from 22 ± 5% to 4± 1% in the case of anti-TNF-α antibodies and 28±5% to 13±4% with anti-IL-1β antibodies. Similarly, the glomerular neutrophil infiltrate was also reduced by these treatments; from 42±3 to 25±1 in the case of anti-TNF-α and 47± 2 to 30± 1 with anti-IL-1α antibodies. In contrast, passive immunization against IL-1α had no effect on either albumin excretion (4±3, 83±22 and 77±24 mg/24 h), glomerular capillary thrombi (2±1; 19±5 and 16±3) or glomerular neutrophil infiltrate (22± 3; 47± 5 and 48± 5 from the three groups respectively). These results demonstrate that enhanced antibody mediated injury in the kidney is modulated by TNF-α and IL-14bT but not by IL-lα.

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

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