W22 - Kv1.3−/− Mice Do Not Develop CIA: A Novel Target with Small Molecules for Autoimmune Arthritis

Engagement of the T cell receptor triggers Ca⁺⁺ influx. This Ca⁺⁺ influx is only possible with a counterbalancing K⁺ efflux through Kv1.3 and/or KCa3.1 channels. Given its regulatory role in the effector memory-T cells (TEM), Kv1.3 is likely to play a critical role in T cell mediated autoimmune arthritis (e.g.; rheumatoid arthritis(RA), psoriatic arthritis). Here using Kv1.3^−/− mice we are reporting that functional Kv1.3 channels are critical for induction of collagen induced arthritis(CIA).

Kv1.3^−/− mice are on the C57BL/6 background so we used C57BL/6 mice to induce CIA. CIA was induced in Kv1.3^−/− mice and in C57BL/6 wild-type (n=10,each).

Kv1.3^−/− mice did not develop arthritis; whereas, about 60% of the wild-type C57BL/6 mice had arthritis. Clinical and histopathological scores for arthritis on day-60 was zero in the Kv1.3^−/− mice. In wild-type mice the respective scores were 2.8±0.5 and 6.2±1.5 (p< .01). Evidence of arthritis was further confirmed/quantified by micro-PET imaging.

We also observed that knocking out of Kv1.3 renders T cells resistant to activation. A marked proliferation of the mouse splenic CD3⁺ T cells with CD3/CD28 ab in the wild type C57BL/6J was noticed compared to the Kv1.3 KO (p< .01); this was demonstrated by more generations of cells and an increased number of cells in each generation.

These observations substantiate a critical role of the Kv1.3, a voltage-gated K⁺ channel in the pathogenesis of T cell mediated autoimmune arthritis including RA. These results provide a platform to develop small molecule-based novel Kv1.3 antagonists (e.g., PAP-1) for treatment of RA.