Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with Granulomatosis with polyangiitis

by Selleckchem | May 19 2023

Objectives: Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory as it relies on strong immunosuppressive regimens, with either cyclophosphamide or rituximab, that reduce the immunogenicity of several vaccines and are risk factors of severe form of COVID-19. This emphasizes the need to identify new drug target and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186.

Methods: Peripheral blood of 27 GPA-patients in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with PMA, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+TH cells were assessed using flow cytometry.

Results: ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17, and IL-21 in CD4+TH cells from GPA-patients in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs.

Conclusions: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Comments：

Summary:

The study aimed to evaluate the potential of Kv1.3 blockade using the specific peptide inhibitor, ShK-186, to modulate the activity of CD4+ effector memory T cells (TEM) in GPA-patients. Peripheral blood from 27 GPA-patients and 16 healthy controls were pre-incubated in vitro with ShK-186, followed by stimulation with PMA, calcium ionophore, and brefeldin-A. Flow cytometry was used to assess the effect of ShK-186 on the cytokine production within total and subsets of CD4+TH cells. The results demonstrated that ShK-186 reduced the expression level of pro-inflammatory cytokines in CD4+TEM cells, which play a key role in the pathogenesis of GPA. This suggests that modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Key Findings:

ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17, and IL-21 in CD4+TH cells from GPA-patients in vitro.
ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells.
ShK-186 treatment reduced the production of pro-inflammatory cytokines to the level seen in CD4+ TH cells from healthy controls.
Implications:

The findings of this study suggest that Kv1.3 blockade using ShK-186 may be a potential treatment strategy for GPA. By modulating the activity of CD4+TEM cells, ShK-186 may reduce the production of pro-inflammatory cytokines, which play a key role in the pathogenesis of GPA. Since the current treatment of GPA relies on strong immunosuppressive regimens, which are associated with harmful side effects, ShK-186 may offer a less harmful treatment option. However, further studies are needed to evaluate the efficacy and safety of ShK-186 in GPA-patients.