Selective inhibition of Kv1.3 channels in memory T cells by targeted delivery with nanoparticles suppresses CD40 ligand expression in SLE (THER5P.908)

Abstract

Abstract The pathogenesis of Systemic Lupus Erythematosus (SLE) is characterized by hyperactive memory T cells (TM). In SLE, the TM cells show a Ca2+-dependent increase in the costimulatory CD40 ligand (CD40L) which binds CD40 on B cells, resulting in B cell activation and autoantibody production. CD40L is widely recognized as a potential target for developing new therapies for SLE. Cytosolic Ca2+ levels, which increase during T cell activation and mediate CD40L expression, are regulated by Kv1.3 channels. We have developed lipid nanoparticles that can deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to TM cells and decrease the activation-induced Ca2+ influx (Hajdu et al., Biomaterials 2013). We studied whether these Kv1.3-NPs decrease the Ca2+-dependent overexpression of CD40L in SLE peripheral blood TM cells. We observed that nuclear translocation of NFAT, a transcription factor upstream to CD40L, in activated TEM cells was reduced by ~50% after treatment with Kv1.3-NPs. Furthermore, Kv1.3-NP treatment selectively reduced CD40L expression in activated TEM cells by ~40% in healthy donors and ~60% in SLE patients, while CD40L levels remained unchanged in cells that did not incorporate the nanoparticles. Interestingly, we observed that treatment with Kv1.3-NPs in SLE patients resulted in T cell phenotype switching from a predominantly TM phenotype to a naïve phenotype. Our findings open the possibility of using Kv1.3-NPs as potential targeted immune suppressive therapeutic agents in SLE.