Kidney Week

Abstract: SA-PO461

Targeting Immunosuppressive Pathways Reduces ADPKD Progression in a Relevant Murine Model

Session Information

• Cystic Kidney Diseases: Basic/Translational
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Nguyen, Dustin, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Dustin Nguyen,

• Kleczko, Emily K., University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Emily K. Kleczko,

• Gitomer, Berenice Y., University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Berenice Y. Gitomer,

• Clambey, Eric T., University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Eric T. Clambey,

• Chonchol, Michel, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol,

• Klawitter, Jelena, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Jelena Klawitter,

• Nemenoff, Raphael A., University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Raphael A. Nemenoff,

• Hopp, Katharina, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, United States

Katharina Hopp,

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) shares many parallels with cancer, where tumor microenvironmental immune cells considerably impact disease progression. Similarly, both macrophages and T cells within the cystic microenvironment (CME) regulate cystogenesis in ADPKD murine models. But, how the interplay among these cells impacts cyst progression remains elusive. The goal of this study was to understand this dynamic interplay better.

Methods

We utilized flow cytometry to quantify renal immune cells in the murine ADPKD C57Bl/6 Pkd1 p.R3277C (RC) model, strain matched wildtypes (WT), and Pkd1 RC mice treated with either an inhibitor to the CSF1 receptor (CSF1R) or IDO1 (treatment regimen: 30 days starting at 1-month of age). CSF1 binding to CSF1R regulates macrophage proliferation and IDO1 regulates T cell function.

Results

IDO1 levels were increased in our Pkd1^RC/RC mice, a Pkd1^-/- cell line, and in ADPKD patient cyst cells vs. controls. Further, resident macrophage numbers were significantly increased in Pkd1^RC/RC vs. WT mice. These findings led us to investigate if CSF1R or IDO1 inhibition slows ADPKD and how targeting different immune cell populations modulates the CME. Intriguingly, blocking of either protein reduced PKD severity (%kidney weight [W]/body W) in our mild, slowly progressive model and altered the CME significantly. Both treatments significantly reduced renal resident but not infiltrating macrophage as well as T cell numbers; renal neutrophil or dendritic cell numbers were not impacted. Most interestingly, while overall significantly reduced, the CD4 T cell population shifted, with regulatory T cells (T_Regs; known to be immunosuppressive) being significantly reduced two-fold by both treatments. This is of notable importance as we found T_Regs to be significantly enriched four-fold in the CD4 population in early disease when comparing Pkd1^RC/RC vs. WT mice.

Conclusion

Using a relevant disease model, we show that targeting resident macrophages or modulators of T cell function can reduce PKD progression. Inhibition of both pathways resulted in reduced numbers of renal T_Regs, suggesting that they may be a unifying key effector of cystogenesis and a viable target for ADPKD immune therapy.

Funding

• NIDDK Support