Modulation of T and B cell function in Granulomatosis with polyangiitis: Targeting Kv1.3 potassium channels

Granulomatosis with polyangiitis (GPA) is a chronic systemic autoimmune disease characterized by inflammation of small blood vessels predominantly in the upper and lower respiratory tract and/or kidney. Current treatment with immunosuppressants succeeds in establishing disease remission in most patients. However, 50% of patients experience disease relapses during their disease course. Each relapse is accompanied by increased organ damage and loss of quality of life. In particular, generalized immunosuppressive therapies used induce adverse events and cause increased risk for opportunistic infections. This emphasizes the need for novel immunomodulators with more specific and less toxic treatment regimens for GPA-patients.
Considerable evidence supports a key role for B- and T-cells in the pathogenesis of GPA. In this thesis, we have demonstrated that the distribution of effector memory T- and B-cells in the circulation of GPA-patients is altered. Differences in effector memory T-cell phenotypes were associated with various clinical presentations of the disease which were influenced by CMV infection. Interestingly, it has been shown that effector T- and B-cells express high levels of a specific Kv1.3 potassium channel that may serve as a selective therapeutic target. Indeed, in vitro blockade of these channels with the highly potent Kv1.3 channel inhibitor ShK-186 modulated T-cell function in GPA-patients resulting in normalization of pro-inflammatory cytokine production. For B-cells, antibody dependent and independent effector functions were suppressed by ShK-186, skewing B-cell responses towards a more prominent regulatory response. In conclusion, selective Kv1.3 channel blockade using ShK-186 may be an attractive therapeutic option for T and B effector subset-selective immunomodulation in GPA.