Kidney Week

Abstract: TH-PO589

Neutralization of Programmed Death Ligand 1 Delays Cyst Growth in ADPKD

Session Information

• Cystic Kidney Diseases - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Peda, Jacqueline D., Kidney Institute at the University of Kansas Medical Center, Kansas City, Kansas, United States

Jacqueline D. Peda,

• Marilovtseva, Ekaterina, Kidney Institute at the University of Kansas Medical Center, Kansas City, Kansas, United States

Ekaterina Marilovtseva,

• Li, Xiaoyan, Kidney Institute at the University of Kansas Medical Center, Kansas City, Kansas, United States

Xiaoyan Li,

• Calvet, James P., Kidney Institute at the University of Kansas Medical Center, Kansas City, Kansas, United States

James P. Calvet,

• Li, Xiaogang, Kidney Institute at the University of Kansas Medical Center, Kansas City, Kansas, United States

Xiaogang Li,

Background

Interstitial inflammation plays a significant role in polycystic kidney disease (PKD). This inflammation features macrophages and other inflammatory cells, and cytokines released by these cells can be found in cyst fluid and urine. The Programmed Death 1 (PD1)/PD Ligand 1 (PDL1) pathway is a recent target for the treatment of multiple cancers. The upregulation of PDL1 on the surface of tumor cells due to immune infiltrates acts as a natural ‘balance’ to limit tissue-specific responses to inflammation, limiting T-cell mediated destruction. However, the roles and mechanisms of T-cells and PDL1 in underlying inflammation of ADPKD remain unknown

Methods

To evaluate a potential role of T-cells and PDL1 in cyst immunopathology, we investigated the presence of T-cells in cystic kidneys from Pkd1^flox/flox:Pkhd1-Cre knockout mice using FACS sorting and immunostaining. The expression of PDL1 in cystic renal epithelial cells and tissues was evaluated via immunostaining, protein and RNA expression. A PDL1 neutralizing antibody was used to evaluate its effects on cyst growth in vivo.

Results

We found that T-cells were present in higher levels in cystic kidneys and that they were localized to the interstitium surrounding cystic tissue. We also found that the expression of PDL1 mRNA and protein was increased in Pkd1 mutant renal epithelial cells compared to control cells. Additionally, we detected PDL1 in kidneys of Pkd1 conditional knockout mice, where it was primarily expressed in the cyst-lining epithelia derived from collecting ducts. The expression of PDL1 could be epigenetically regulated and enhanced in response to inflammatory cytokines in cystic renal epithelial cells. We further found that neutralizing PDL1 with a monoclonal antibody, which is well tolerated and currently being studied in late phase cancer trials, delayed cyst growth. This was reflected by decreased cystic index and kidney weight (KW)/body weight (BW) ratios in Pkd1 conditional knockout mice compared to untreated mice. Effects on disease progression is likely due to blocking the PDL1 interaction with PD1 on T-cells.

Conclusion

This is the first report that T-cells are present in higher numbers in cystic kidneys when compared to controls, and that PDL1 is uniquely expressed in non-cancerous renal epithelial cells. Blockade of PDL1 interaction with T-cells may prove therapeutic in ADPKD.

Funding

• NIDDK Support