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Kidney Week

Abstract: FR-OR081

Investigating the Role of CD40-CD154 Interactions in Lupus Nephritis

Session Information

  • Lupus and Then Some
    November 08, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
    Abstract Time: 04:30 PM - 04:42 PM

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Rush, James, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Nuesslein-Hildesheim, Barbara, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Lafossas, Frédérique, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Wieczorek, Grazyna, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Ceci, Melanie, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Gaulis, Swann, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Palla, Giovanni, Novartis Institute for BioMedical Research, Basel, Switzerland
  • Mcmichael, Katriona, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Ferrero, Enrico, Novartis Institutes for Biomedical Research, Basel, Switzerland
  • Pfister, Sabina, Novartis Pharma AG, Basel, Switzerland
Background

Disease pathology in lupus nephritis (LN) has been linked to a variety of different immune pathways, including CD40-CD154 interactions. This pathway has been shown to regulate the activation of B lymphocytes as well as macrophages and activated renal epithelia, and thus blockade of this pathway could provide therapeutic benefit in individuals with LN.

Methods

We evaluted the expression and activation of the CD40-CD154 pathway in kidney tissue from LN patients. Additionally, we evaluted the therapeutic effect of a blocking, non-depleting anti-mouse CD40 mAb (GOT40) in the NZB/W F1 model of lupus nephritis.

Results

Histological analysis of kidney biopsies from patients with proliferative LN revealed evidence of CD40 and CD154 on B cells, macrophages and T cells respectively. These results suggested that there might be ongoing T-B cell collaboration in LN kidneys and we subsequently examined whether there was evidence of CD40 pathway expression and activation in situ. Using published scRNA-seq data from LN kidney biopsies we could demonstrate evidence of CD40 transcript expression by B cells and myeloid cells and CD154 expression by subsets of CD4+ T cells. To directly address the role of CD40-CD154 in LN, we used GOT40, a novel, blocking, non-depleting anti-CD40 antibody in the NZB/W F1 model of lupus nephritis. Therapeutic treatment for 9-77 days of NZB/W F1 mice aged 24 to 37 weeks and individually enrolled into treatment groups with proteinuria ≥3 mg/ml resulted in suppression of established proteinuria and extended survival in GOT40 treated animals in comparison to isotype control treated animals. Serum autoantibody and CXCL13 levels were reduced by GOT40 treatment compared to isotype control. Similar to current treatments, we observed only minimal (not significant) reduction in various histological parameters with GOT40 treatment at this advanced stage of kidney injury, despite evidence of complete, systemic pathway blockade at the transcriptional level and suppression of a kidney gene expression with GOT40 treated animals.

Conclusion

Our data support the notion that CD40-CD154 pathway signaling may contribute to pathology in LN and that anti-CD40 treatment could provide therapeutic benefit in individuals suffering from this disease.

Funding

  • Commercial Support