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Abstract: FR-PO600

Immune Checkpoint Molecule BTLA Attenuates Experimental Glomerulonephritis by Directly Inhibiting T Effector Cells and Inducing Treg Differentiation

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Diefenhardt, Paul, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Braumann, Marie, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Trinsch, Bastian, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Schömig, Thomas, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Sierra Gonzalez, Claudio, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Schermer, Bernhard, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Benzing, Thomas, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Brinkkoetter, Paul T., Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Braehler, Sebastian, Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany

Group or Team Name

  • Braehler Lab
Background

Excessive, dysregulated inflammation mediated by T-cells in the kidney can lead to acute, crescentic Glomerulonephritis (GN). After T-cell receptor binding to a specific antigen, secondary and tertiary signals are required for successful T cell activation and differentiation. Accordingly, interference with these additional signals might represent a viable treatment option for GN. One of these secondary signal molecules, B and T Lymphocyte Attenuator (BTLA), was shown to mediate anti-inflammatory effects in other T-cell mediated disease models. Its role during glomerular inflammation, however, remains unclear.

Methods

Nephrotoxic nephritis (NTN) was induced in wild type (wt) and BTLA knock out (BTLA-KO) mice. For treatment evaluation, an agonistic anti-BTLA antibody was administered i.v. into wt mice after NTN induction. Functional readouts included albuminuria and BUN concentration. Histological damage was assessed 10 days after NTN induction in all groups using PAS stained tissue slides. Extensive immunophenotyping of renal and splenic immune cells was performed using IHC and flow cytometry. Additional in vitro assays revealed the impact of BTLA deficiency on the function of dendritic cells and T-cell subsets.

Results

Knockout of BTLA results in aggravation of NTN driven by an increase in pro-inflammatory Th1 cells. Systemically, nephritic BTLA-KO mice show a significant reduction of T regulatory cells. Activation of BTLA through administration of an agonistic anti-BTLA-antibody attenuate NTN by reducing the frequencies of Th1 and Th17 cells in the nephritic kidney and increasing systemic Treg numbers. In vitro Treg suppression assays reveal an evasion of Treg mediated suppression by BTLA deficient T effector cells. Suppressive capacity of BTLA deficient Tregs, on the other hand, is unchanged. Likewise, no impairment of T-cell activation by BTLA deficient DCs was detected.

Conclusion

BTLA attenuates inflammation in experimental GN through two mechanisms: 1) via Treg mediated suppression of BTLA+ T effector cells and 2) through induction of anti-inflammatory T regulatory cells. Activation of BTLA signaling by agonistic antibodies represents an effective treatment strategy in NTN.