Kidney Week

Abstract: TH-OR057

Induction of a Glomerular Reparative Program in Lupus Glomerulonephritis by a Novel Treg-Enhancing Cytokine Therapy

Session Information

• Glomerular Diseases: Spotlighting Immunology and Inflammation - I
  October 25, 2018 | Location: 8, San Diego Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Venkatadri, Rajkumar, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Rajkumar Venkatadri, PhD

• Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Vikram Sabapathy,

• Stremska, Marta, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Marta Stremska,

• Wang, Hongyang, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Hongyang Wang,

• Sung, Sun-sang J., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Sun-sang J. Sung,

• Mohammad, Saleh, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Saleh Mohammad,

• Fu, Shu man, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Shu man Fu,

• Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Rahul Sharma,

Background

Lupus glomerulonephritis (GN) is an autoimmune disease marked with glomerular inflammation and with reduced levels of IL-2 and T-regulatory cell as contributing factors. Earlier we showed that a novel hybrid cytokine IL233 utilizes the synergy of IL-2 and IL-33 to increase Tregs and protect mice from acute kidney injury and onset of accelerated GN in lupus prone NZM2328 mice. Here we investigated whether IL233 can reverse ongoing lupus GN and restore renal structure and function.

Methods

We made use of the recombinant hybrid cytokine (IL233) bearing activities of IL-2 and IL-33 and tested its efficacy to induce a glomerular repair program in three animal model systems: spontaneous lupus GN in NZM2328, adenovirus (Ad)-IFNa-accelerated lupus GN model and MRL/lpr mice.

Results

Treatment of NZM2328 mice after the onset of GN, induced rapid and persistent remission from severe proteinuria in Ad-IFNa-accelerated GN in NZM2328 mice as well as spontaneous lupus GN in NZM2328 and MRL/lpr mice. IL233 strongly inhibited glomerular hypertrophy and mesangial expansion and induced skewing of immune complex deposits towards IgG2b as compared to predominantly IgG2a deposits in control mice. Markers of glomerular integrity (nephrin, podocin, podocalyxin and synaptopodin) were elevated in IL233 treated animals confirming its therapeutic effects. Furthermore, IL233 treatment in mice with established GN also induced elevated levels of renal progenitor markers (Sox9, Six2, Lgr4, Lgr5 and Pax8) indicating an IL233-mediated cellular programming involving regeneration and repair.

Conclusion

We present a novel cytokine therapy of lupus GN with implications for induction of a glomerular reparative program with the use of IL233 hybrid cytokine.

Funding

• Other NIH Support