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Murine Model of CD40-activation of B cells
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Murine Model of CD40-activation of B cells

Published on: March 5, 2010

The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis

Vincent W S Lee1, Xiaohong Qin, Yiping Wang

  • 1Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia. vincent_lee@wmi.usyd.edu.au

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
|November 6, 2009
PubMed
Abstract

Insights

CD40-CD154 blockade offers innate protection against adriamycin-induced kidney injury in mice, even without adaptive immunity. This effect may stem from reduced macrophage infiltration and inflammatory responses.

Area of Science:

  • Immunology
  • Nephrology
  • Pharmacology

Background:

  • CD40-CD154 blockade previously showed renal protection in adriamycin nephropathy (AN) in immunocompetent mice.
  • The role of adaptive versus innate immunity in this protection was unclear.
  • This study investigated CD40-CD154 blockade in severe combined immunodeficient (SCID) mice to elucidate the immune mechanisms involved.

Purpose of the Study:

  • To determine if CD40-CD154 blockade protects against adriamycin nephropathy (AN) in SCID mice, which lack adaptive immunity.
  • To investigate the innate immune mechanisms underlying the renoprotective effects of CD40-CD154 blockade.
  • To assess the impact of CD40-CD154 blockade on macrophage infiltration and inflammatory gene expression in the kidney.

Main Methods:

  • SCID mice were induced with adriamycin (ADR) and treated with either control IgG or anti-CD154 antibody (MR1).
  • Renal function and histology were assessed four weeks post-ADR injection.
  • In vitro studies examined the effect of CD154 blockade on CD40-expressing renal cells (macrophages, mesangial cells, RTEC) and platelet-induced inflammation.

Main Results:

  • ADR-induced nephropathy occurred in all groups; however, MR1 treatment significantly reduced histological and functional renal injury compared to controls.
  • MR1 treatment led to decreased macrophage infiltration in the kidneys.
  • In vitro, CD154 blockade attenuated CCL2 gene expression in RTEC stimulated by macrophages, but did not affect platelet-induced cytokine expression.

Conclusions:

  • CD40-CD154 blockade confers a significant innate renoprotective effect in adriamycin nephrosis.
  • This protection is likely mediated by the inhibition of macrophage-derived soluble CD154, independent of adaptive immunity.
  • The findings highlight the potential of targeting the CD40-CD154 pathway for treating kidney diseases involving innate immune responses.

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