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Kidney Week

Abstract: PO1423

Pulsed Steroids Impede T Memory Cell Recruitment to the Kidney in Human and Experimental Crescentic Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Riedel, Jan-Hendrik, III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Wiech, Thorsten, Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Krebs, Christian F., III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Panzer, Ulf, III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background

Despite undesirable side effects and understudied modes of action steroids still constitute a cornerstone of therapeutic regimes for autoimmune kidney diseases presenting as rapidly progressive glomerulonephritis (RPGN), e.g. anti-neutrophil cytoplasmatic antibody associated glomerulonephritis (ANCA-GN). However, if the rapid clinical effects of steroids are due to a direct impact on leukocytes, i.e. CD3+ T cells, or mediated indirectly by attenuation of an inflammatory environment is still unknown.

Methods

Kidney biopsies of patients with ANCA-GN with and without pulsed steroids before biopsy were analysed by immunohistochemistry, flow cytometry and single cell RNA sequencing. Furthermore, corresponding studies were conducted in untreated or steroid pulsed mice with crescentic glomerulonephritis (cGN), respectively. Additionally, steroid effects were studied in mice lacking the glucocorticoid receptor specifically in T cells and in CD4+ T cell transfer experiments in nephritic recombination activating gene 1 (RAG1) knockout mice.

Results

Combined high-dimensional single-cell analysis and IHC showed that intravenous steroid pulses rapidly reduced renal T-cell infiltrate in human ANCA-GN patients but did not significantly regulate the immune response of a specific T-cell subset (e.g., Th1, Th2, Th17, Treg). Almost identical effects were observed in a murine cGN model (nephrotoxic nephritis), including reduced glomerular crescent formation, after steroid pulse treatment. Functional studies using CD4+ T-cell-specific glucocorticoid receptor-deficient mice showed that T-cell reduction was not caused by T-cell-intrinsic factors. Mechanistically, we demonstrated in CD4+ T-cell transfer experiments that steroid-induced attenuation of intrarenal effector T cells in cGN was a consequence of reduced expression of the T-cell-attracting chemokines CCL5, CCL20, CXCL9, and CXCL10 by resident kidney cells, which was further confirmed by in vitro and ex vivo trafficking experiments.

Conclusion

Our findings demonstrate that pulse steriod therapy rapidly reduce renal T-cell infiltrate in human and murine cGN by inhibiting the production of T-cell-attracting chemokines by resident renal cells. In summary, we have identified a previously unrecognized therapeutic mechanism of steroids in immune-mediated glomerular disease.

Funding

  • Government Support – Non-U.S.