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Abstract: TH-PO536

Modified Immune Cell (MIC) Therapy Disrupts Tertiary Lymphoid Structures in Murine Lupus Nephritis

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • Ponath, Gerald, TolerogenixX GmbH, Heidelberg, Germany
  • Speer, Claudius, University of Heidelberg, Department of Nephrology, Heidelberg, Germany
  • Arnold, Iris I., University of Heidelberg, Department of Nephrology, Heidelberg, Germany
  • Hidmark, Asa, TolerogenixX GmbH, Heidelberg, Germany
  • Wang, Lei, TolerogenixX GmbH, Heidelberg, Germany
  • Kleist, Christian, University of Heidelberg, Department of Nuclear Medicine, Heidelberg, Germany
  • Schmitt, Anita, University of Heidelberg, Department of Internal Medicine V, Heidelberg, Germany
  • Daniel, Volker, TolerogenixX GmbH, Heidelberg, Germany
  • Opelz, Gerhard, TolerogenixX GmbH, Heidelberg, Germany
  • Terness, Peter, TolerogenixX GmbH, Heidelberg, Germany
  • Schmitt, Michael, University of Heidelberg, Department of Internal Medicine V, Heidelberg, Germany
  • Zeier, Martin G., University of Heidelberg, Department of Nephrology, Heidelberg, Germany
  • Morath, Christian, University of Heidelberg, Department of Nephrology, Heidelberg, Germany
  • Schaier, Matthias, University of Heidelberg, Department of Nephrology, Heidelberg, Germany
Background

Induction of tolerance can be achieved with Modified Immune Cells (MIC) by infusion of mononuclear cells challenged with mitomycin C (MMC). Although MIC treatment has been successful in several animal models for autoimmunity and in clinical studies of solid organ transplantation, the mechanism of immunosuppression is not fully elucidated.
In lupus nephritis, the glomerular deposition of immune complexes is associated with accumulating immune cells in the kidney. The infiltrating immune cells frequently establish tertiary lymphoid structures (TLS) supporting adaptive autoimmune responses toward locally displayed antigens.
Since TLS display a high persistence to peripheral B cell depletion, the destruction of TLS presents an essential treatment goal in lupus nephritis. In this study, we used lupus nephritis prone NZB/W F1 mice to show the destruction of TLS in the kidney after MIC treatment.

Methods

Splenocytes of syngeneic donor mice were incubated with MMC and injected into recipient’s tail vein after matching for disease activity. Disease activity was monitored by body weight, protein excretion, serum creatinine and dsDNA. Kidney histopathology was performed by immunofluorescent microscopy. Densitometric measurement of regulatory markers in immune cell subsets were computationally quantified.

Results

Independent of treatment, >86% of animals displayed dense lymphocytic aggregates proximal to the pelvic wall of the medulla and the arcuate arteries within the cortex of kidneys. Cell type composition of TLS changed drastically after MIC treatment leading to diminished B-cells, a decreased B-cell/T-cell ratio, and a T cell dominated phenotype. Furthermore, a loss of organization of the TLS was observed after MIC treatment. The strict separation of B-cell and T-cell areas was abrogated, and germinal centers were disintegrated. However, regulatory T-cells remained unchanged indicative of a B-cell centric treatment mechanism.

Conclusion

Our data provides a putative in vivo mechanism how MIC treatment inhibits progression of active lupus nephritis by the destruction of tertiary lymphoid structures within the kidney.

Funding

  • Commercial Support