Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

Science Advances
Marat KhodounLaura Conforti

Abstract

Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8+ Tm cells expressing high voltage-dependent Kv1.3 potassium channels-key T cell function regulators-in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells (Kv1.3-NPs) reduced CD40L and interferon-γ (IFNγ) in Tm cells from LN patients in vitro. Kv1.3-NPs were tested in humanized LN mice obtained by engrafting peripheral blood mononuclear cells (PBMCs) from LN patients into immune-deficient mice. LN mice exhibited features of the disease: increased IFNγ and CD3+CD8+ T cell renal infiltration, and reduced survival versus healthy donor PBMC engrafted mice. Kv1.3-NP treatment of patient PBMCs before engraftment decreased CD40L/IFNγ and prolonged survival of LN mice. These data show the potential benefits of targeting Kv1.3 in LN.

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Citations

Dec 5, 2020·Nature Reviews. Nephrology·Ellen F Carney
Dec 11, 2020·Nature Reviews. Rheumatology·Ellen F Carney
Apr 6, 2021·Molecular Therapy. Methods & Clinical Development·Hannah S NewtonLaura Conforti
Jun 30, 2021·Current Opinion in Rheumatology·Ping-Min Chen, George C Tsokos

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Methods Mentioned

BETA
biopsies
biopsy
Fluorescence
flow cytometry
nuclear translocation
density gradient centrifugation
enzyme-linked immunosorbent assay
ELISA

Software Mentioned

Leica Application Suite X
Image J
nCounter Advanced Analysis
SigmaPlot
nCounter
ImageJ
Canopy
FlowJo

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