In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular a
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(2020) 68:31
ORIGINAL ARTICLE
In Mixed Lymphocyte Reaction, the Hypoxia‑Inducible Factor Prolyl‑Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity Theodoros Eleftheriadis1 · Georgios Pissas1 · Athanasios Mavropoulos1 · Evdokia Nikolaou1 · Georgios Filippidis1 · Vassilios Liakopoulos1 · Ioannis Stefanidis1 Received: 28 January 2020 / Accepted: 18 September 2020 © L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2020
Abstract Hypoxia-inducible factor (HIF) prolyl-hydroxylase inhibitors are currently used for the treatment of renal anemia. Since HIF affects immune cells, we evaluated the effect of such a drug, the roxadustat, on adaptive immunity. Cell proliferation was assessed in a two-way mixed lymphocyte reaction (MLR) with BrdU assay. In CD4+ T cells isolated from the two-way MLRs, western blotting was performed to detect the impact of roxadustat on HIF-1α and HIF-2α, the apoptotic marker cleaved caspase-3, and the master transcription factors of CD4+ T cells differentiation towards Th1, Th2, Th17, Treg and Tfh subsets. The signature cytokines of the above C D4+ T-cell subsets IFN-γ, IL-4, IL-17, IL-10, and IL-21 were measured in the supernatants. For assessing humoral immunity, we developed a suitable antibody-mediated complement-dependent cytotoxicity assay. Roxadustat stabilized HIF-1α and HIF-2α, suppressed cell proliferation, inhibited CD4+ T-cell differentiation into Th1 and Th17 subsets, while it favored differentiation towards Th2, Treg and Tfh. Roxadustat suppressed humoral immunity too. These immunosuppressive properties of roxadustat indicate that the recently introduced HIF prolylhydroxylase inhibitors in medical therapeutics may render the patients vulnerable to infections. This possibility should be further evaluated in clinical trials. Keywords Roxadustat · Hypoxia-inducible factor · Cellular immunity · Humoral immunity · T-cell differentiation
Introduction Hypoxia-inducible factor (HIF) prolyl-hydroxylases (PH) inhibitors are a new class of drugs currently tested for the treatment of anemia in patients with chronic kidney disease (Gupta and Wish 2017). Roxadustat is a HIF-PH inhibitor, which has already completed the related phase III clinical trials and been approved for clinical use in China and Japan (Akizawa et al. 2020; Chen et al. 2019). By inhibiting PH, this class of drugs prevents HIF-2α hydroxylation and its subsequent E3 ubiquitin ligase Von Hippel–Lindau (VHL)mediated ubiquitination and proteasomal degradation. The accumulated ΗIF-2α increases erythropoietin production (Gupta and Wish 2017). Also, HIF-PH inhibitors enhance * Theodoros Eleftheriadis [email protected] 1
Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
HIF-1α level altering the expression of specific iron handling proteins, improving iron metabolism, and eventually, favoring erythropoiesis (Eleftheriadis et al. 2016a; Gupta and Wish 2017). Besides genes implicated in erythro
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