Abstract: TH-PO327

A Novel Hybrid Multifunctional Cytokine IL233 Promotes Regeneration Following Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
  • Cheru, Nardos Tesfaye, University of Virginia, Charlottesville, Virginia, United States
  • Corey, Rebecca L, University of Virginia, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
Background

Nephrotoxicity remains a principle concern among complications arising due to chemotherapy. For many chemotherapeutic agents and their metabolites, kidney remains the main pathway for elimination. Inflammation amplifies the renal injury and studies have demonstrated that regulatory T-cells (Treg) play a vital role in restricting inflammation thus facilitating recovery following injury. Based on our studies that interleukin IL-2 and IL-33 synergize to increase the number and function of Tregs, we generated a hybrid cytokine (IL233) bearing the activities of both cytokines in one molecule. Pretreatment with IL233 increased Tregs and protected mice from ischemia reperfusion injury (J Am. Soc. Neph., 2017). Here, we investigated, whether the IL233-mediated increase in Tregs can be used therapeutically in nephrotoxic injury model and whether it promotes renal repair.

Methods

The cytokine overexpressed in E.coli were purified using affinity and ion-exchange chromatography. A murine model of doxorubicin-induced renal injury was developed to investigate the therapeutic effect of the cytokine. BALB/cJ male mice were injected with doxorubicin (iv) and the protective effect of the cytokine treatment (ip) was examined both pre- and post- doxorubicin administration. The structure and function of the kidney were probed using flow cytometry, histology, immunohistochemistry, quantitative gene expression analysis and biochemical analysis.

Results

As expected, cytokine treatment rapidly increased Treg numbers in blood and spleen. Mice treated with IL233 hybrid cytokine either before or after doxorubicin treatment had lower kidney injury and inflammation scores. Plasma creatinine and blood urea nitrogen values also indicate that IL233 pretreatment significantly protected renal function. Importantly, IL233 administration post doxorubicin treatment restored the kidney function. The level of renal fibrosis was also significantly less in the treated group than saline group. Treatment with hybrid cytokine led in augmenting the levels of Th2 and anti-inflammatory cytokines but attenuating the pro-inflammatory cytokines.

Conclusion

The data from this study provides that IL233 hybrid cytokine bears strong therapeutic potential to rescue kidney injury associated with nephrotoxic drugs and promote repair.

Funding

  • Other NIH Support