ADPKD: Understanding immunosuppression mechanisms and discovering treatment

总结

Summary The immune system plays an important role in protecting us from disease. Interstitial inflammation has been consistently reported in human and animal models of ADPKD, and it may become worse during cyst expansion which results in more damages in renal parenchyma. In addition to the increase of macrophages in the interstitium and pericystic areas, T lymphocytes are also increased in cystic kidneys. However, whether and how PKD mutant cystic renal epithelial cells escapes immune attacks in cystic microenvironment during cyst initiation and expansion remains elusive. In this study, we investigate the roles of programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1), a PD-1 ligand, in ADPKD. We found that, 1) PD-1 was upregulated on T cells in Pkd1 mutant kidneys; 2) PD-L1 was upregulated in Pkd1 mutant renal epithelial cells and tissues, and was increased in cystic cell derived exosomes; 3) knockout of Pd-l1 delayed cyst growth and increased the survival of Pkd1 knockout mice; 4) targeting PD1 and PD-L1 with antibodies delayed cyst growth in Pkd1 knockout kidneys; 5) treatment with exosomes isolated from cystic renal epithelial cells and urine of ADPKD patients increased Pkd1 wild type renal epithelial cell proliferation, and induced the activation of PKD associated signaling in these cells; 6) treatment with cystic renal epithelial cell derived exosomes promoted cyst growth in Pkd1 mutant kidneys; 7) renal epithelial cells (NRK-52E cells) treated with ADPKD urinary exosomes also developed cysts-like structures in collagen gels; and 8) inhibition of exosome secretion with GW4869 delays cyst growth in Pkd1 knockout kidneys. Our central hypothesis is that upregulation of PD-L1 on cystic renal epithelial cells and PD-1 on T cells results in immune evasion of cystic cells via inhibition of T cell function, and exosomes secreted by cystic renal epithelial cell regulate immunosuppression via adjacent T cells and the function of other neighboring cells, including renal epithelial cells and fibroblasts, contributing to cyst growth. We test this hypothesis with three specific aims. This study will determine for the first time whether PD-1 and PD-L1 are immune-suppressors in cystic kidneys, which helps cystic epithelial cells to escape immune attack in ADPKD, and whether exosomes secreted by cystic epithelial cells contribute to immune suppression and other cellular communication. In addition, we will determine whether PD1 and PD-L1 are effective targets to slow disease progression in preclinical setting. Accomplishing this study will lead to a better understanding of the mechanism of immune surveillance in renal cyst formation and the roles of cystic cell exosomes in regulating immunosuppression and other cell-to-cell communication, which will provide novel therapeutic strategy for ADPKD treatment.