Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Unterweger AL

PROVIDER: S-EPMC8575044 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Unterweger Anna-Lena AL Jensen Morten Ø MØ Giordanetto Fabrizio F Jogini Vishwanath V Rüschher Alena A Seuß Marietta M Winkelmann Paula P Koletzko Leandra L Shaw David E DE Siebeck Matthias M Gropp Roswitha R Beigel Florian F Aszodi Attila A

Journal of Crohn's & colitis 20211101 11

<h4>Background and aims</h4>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.<h4>Methods</h4>Kv1.3 expression on T cells in peripheral blood mo ...[more]

PMID: 33891001

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Dataset Information

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

Background and aims

Methods

Results

Conclusion

Publications

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

Similar Datasets

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