Background/Purpose: TCR (T cell receptor) engagement triggers intracellular Ca⁺⁺ influx through voltage-independent Ca2+ channels. This crucial Ca2+-influx is only possible by a counterbalancing K+ efflux through Kv1.3 and/or KCa3.1. So, these channels are regarded as new targets for immunotherapy: KCa3.1 for acute immune reactions mediated by naïve T cells and Kv1.3 for chronic immune reactions carried by memory T cells. Here we investigated the functional significance of KCa3.1 and Kv1.3 in psoriatic arthritis (PsA) and have used rheumatoid (RA) and osteoarthritis (OA) as controls. To develop K⁺ channel targeted therapies we are working on two small molecules PAP-1 and TRAM-34 which respectively are specific blockers for Kv1.3 and KCa3.1.

Methods: 1. We studied skin tissue, synovial tissue, lymphomononuclear cells (LMNC) from blood and synovial fluid from patients with PsA and RA. In these autoimmune conditions we identified Kv1.3high T cells and determined their phenotypic and functional features. 2. CIA mouse model is a well established tool to study IL-23/IL-17 driven autoimmune arthritis. To determine the functional significance of the KCa3.1 channel CIA was induced in KCa3.1^−/− mice and in C57BL/6 wild type mice.

Results: PsA synovial tissues (n=6) were enriched with Kv1.3+ T cells compared to osteoarthritis (p<.01). Further we noticed KV1.3 K+ channels were functionally active and Kv1.3 current in these T cell could be blocked by PAP-1, a potent small molecule inhibitor of KV1.3 K+ channels. 2. KCa3.1^−/− mice (n=10) failed to develop clinical evidence of arthritis and did not have histological evidence for joint inflammation. Wild-type C57BL/6 mice developed clinical/histopathological evidence of arthritis. Micro-PET imaging as well confirmed these findings. Compared to KCa3.1^−/− mice CD3+ T cell proliferation in response to chicken collagen II (CCII) by MTT assay was significantly higher in the C57BL/6 wild type mice (p<.001). 3. In vitro studies performed with synovial fluid T cells derived from PsA patients demonstrated that the small molecule Kv1.3 blocker PAP-1 dose-dependently inhibited proliferation and suppressed IL-2 and IL-17.

Conclusion: In vitro studies and the in vivo model (PET CIA mouse model) have demonstrated critical roles of the Kv1.3 and KCa3.1 potassium ion channels in the pathogenesis of T cell mediated autoimmune arthritis. Synthetic small molecules PAP-1 and TRAM-34 respectively for Kv1.3 and KCa3.1 have already been studied for safety and tolerability and these T cell ion-channels blockers provide a promising therapeutic approach for psoriatic disease and other T cell mediated human autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-the-voltage-gated-k-channels-t-cell-targeted-therapies-for-spondyloarthritis/