Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanised Mouse Model of Ulcerative Colitis.

Autor: Unterweger AL; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Jensen MØ; D. E. Shaw Research, New York, NY, USA., Giordanetto F; D. E. Shaw Research, New York, NY, USA., Jogini V; D. E. Shaw Research, New York, NY, USA., Rüschher A; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Seuß M; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Winkelmann P; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Koletzko L; Department of Medicine II, University Hospital, LMU Munich, Germany., Shaw DE; D. E. Shaw Research, New York, NY, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Siebeck M; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Gropp R; Department of General, Visceral und Transplantation Surgery, University Hospital, LMU, Munich, Germany., Beigel F; Department of Medicine II, University Hospital, LMU Munich, Germany., Aszodi A; Department of General, Trauma and Reconstructive Surgery, University Hospital, LMU Munich, Germany'.
Jazyk: angličtina
Zdroj: Journal of Crohn's & colitis [J Crohns Colitis] 2021 Nov 08; Vol. 15 (11), pp. 1943-1958.
DOI: 10.1093/ecco-jcc/jjab078
Abstrakt: Background and Aims: The potassium channel Kv1.3 is a potentially attractive therapeutic target in T cell-mediated inflammatory diseases, as the activity of antigen-activated T cells is selectively impeded by Kv1.3 inhibition. In this study, we examined Kv1.3 as a potential therapeutic intervention point for ulcerative colitis [UC], and studied the efficacy of DES1, a small-molecule inhibitor of Kv1.3, in vitro and in vivo.
Methods: Kv1.3 expression on T cells in peripheral blood mononuclear cells [PBMCs] isolated from donors with and without UC was examined by flow cytometry. In biopsies from UC patients, Kv1.3-expressing CD4+ T cells were detected by flow cytometry and immunohistochemistry. In vitro, we determined the ability of DES1 to inhibit anti-CD3-driven activation of T cells. In vivo, the efficacy of DES1 was determined in a humanised mouse model of UC and compared with infliximab and tofacitinib in head-to-head studies.
Results: Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of TH1 and TH2 T cells. Kv1.3 expression was also detected on T cells from biopsies of UC patients. In vitro, DES1 suppressed anti-CD3-driven activation of T cells in a concentration-dependent manner. In vivo, DES1 significantly ameliorated inflammation in the UC model and most effectively so when PBMCs from donors with higher levels of activated T cells were selected for reconstitution. The efficacy of DES1 was comparable to that of either infliximab or tofacitinib.
Conclusion: Inhibition of Kv1.3 [by DES1, for instance] appears to be a potential therapeutic intervention strategy for UC patients.
(© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)
Databáze: MEDLINE
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