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Immune checkpoint activity regulates polycystic kidney disease progression

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8(+) T cells and slow tumo...

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Detalles Bibliográficos
Autores principales: Kleczko, Emily K., Nguyen, Dustin T., Marsh, Kenneth H., Bauer, Colin D., Li, Amy S., Monaghan, Marie-Louise T., Berger, Michael D., Furgeson, Seth B., Gitomer, Berenice Y., Chonchol, Michel B., Clambey, Eric T., Zimmerman, Kurt A., Nemenoff, Raphael A., Hopp, Katharina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371237/
https://www.ncbi.nlm.nih.gov/pubmed/37345660
http://dx.doi.org/10.1172/jci.insight.161318
Descripción
Sumario:Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8(+) T cells and slow tumor growth. We have previously shown that in PKD, CD8(+) T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1(RC/RC) mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti–PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti–PD-1 plus anti–CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8(+) T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.