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Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanized 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 humanized mouse model of UC and compared to 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 |

REPOSITORIES: biostudies-literature

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