Abstract: FR-PO688

Robust Improvement in Lupus Nephritis after Hyaluronidase Treatment Due to the Removal of Accumulated Hyaluronic Acid in Glomerular Endothelial Glycocalyx

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Kadoya, Hiroyuki, University of Southern California, Los Angeles, California, United States
  • Jacob, Chaim O., University of Southern California, Los Angeles, California, United States
  • Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States
Background

Lupus Nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus. The exact pathomechanism of LN has been elusive, and therefore current non-specific therapies are limited to general immunosuppression. Recently, we developed an intravital multiphoton microscopy (MPM) imaging approach to visualize the interplay between cellular components of the immune system and local kidney tissue factors. We observed the glomerular homing of IL-17-producing activated memory T cells, which were the vast majority of all immune cells found in LN kidney. The present study tested the hypothesis that T cell homing is due to the accumulation of the CD44 ligand hyaluronic acid (HA) in the glomerular endothelial glycocalyx, and its removal by hyaluronidase improves LN.

Methods

Serial MPM was used to track the fate of endogenous T cells labeled with anti-CD3 and anti-CD44 antibodies in vivo in a model of rapid LN (BAFF transgenic New Zealand mixed (NZM) mice). FITC-labeled wheat germ agglutinin (WGA) lectin and Alexa594-labeled HA-binding protein (HABP) were used to evaluate glomerular endothelial glycocalyx and HA content, respectively.

Results

Glomerular size, microthrombi, albumin leakage, T cell homing were significantly increased at 4-6 weeks old LN mice compared with control healthy mice. Robust accumulation of endothelial glycocalyx and HA content (thickness and intensity of WGA and HABP fluorescence, respectively) were observed in LN mice, but not in control. Hyaluronidase injection significantly and dose-dependently (EC50=20U) reduced WGA and HABP fluorescence, T cell homing, and albumin leakage within 1 hour. Hyaluronidase treatment caused a 5-fold reduction in albuminuria and 4-fold increase in survival rate of LN mice.

Conclusion

Our results support the major importance of HA in the endothelial glycocalyx in the glomerular homing of memory T cells in the development and pathobiology of LN. Hyaluronidase treatment is a promising new therapeutic approach for LN.