Background/Purpose: Granulomatosis with polyangiitis (GPA) patients are often treated with immunesuppressives or B cell depleting therapy. While B cells are involved in GPA pathogenesis as precursors of anti-neutrophil cytoplasmic antibody (ANCA) producing plasma cells, they can also exert cytokine dependent pro-inflammatory and regulatory functions. In GPA, treatment strategies could be improved by selective targeting of the effector function of B cells. Here, we investigated the effect of the Kv1.3 channel blocker dalazatide (formerly ShK-186) on effector and regulatory B cell function.

Methods: The distribution of B cell subsets was determined in peripheral blood samples of 33 GPA patients and 17 matched healthy controls (HC). Peripheral blood mononuclear cells (PBMC) from GPA patients and HC were stimulated in vitro with CpG-ODN or a combination of CpG, B cell activating factor (BAFF) and interleukin(IL)-21 in the presence and absence of dalazatide. The production levels of total IgG and PR3-ANCA IgG in culture supernatants were analysed by ELISA and Phadia EliA, respectively. In addition, the effect of dalazatide on B cell proliferation and cytokine production was determined by flow cytometry.

Results: Circulating switched and unswitched memory B cells were relatively decreased in GPA patients as compared to HC. Treating stimulated PBMCs with dalazatide resulted in decreased production of both total and PR3-ANCA IgG. Proliferation of B cells was not affected by dalazatide. A strong decrease in production of the pro-inflammatory cytokines TNFα, IL2 and IFNγ was observed with dalazatide treatment. While IL10 production was also decreased with dalazatide treatment in GPA patient samples, this effect was less pronounced. As such, dalazatide modulated the TNFα/IL10 ratio among the B cells, resulting in a relative increase in the regulatory B cell pool.

Conclusion: Dalazatide clearly modulates the effector function of B cells in vitro, by decreasing autoantibody production and the release of pro-inflammatory cytokines. Kv1.3 channel blockade may hold promise as a novel therapeutic strategy in GPA and other B cell mediated autoimmune disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kv1-3-channel-blockade-modulates-the-effector-function-of-b-cells-in-granulomatosis-with-polyangiitis/