Frederic Risch (Bonn / DE), Dr. Johanna Scheunemann (Bonn / DE), Dr. Julia Reichwald (Bonn / DE), Benjamin Lenz (Bonn / DE), Dr. rer. nat. Alexandra Ehrens (Bonn / DE), Marianne Koschel (Bonn / DE), Prof. Achim Hörauf (Bonn / DE), Prof. Dr. Marc P. Hübner (Bonn / DE)
Abstract text
Introduction
Filarial worms can cause debilitating diseases such as lymphatic filariasis and onchocerciasis. Control of both diseases occurs mainly via mass drug administration (MDA), but there are no drugs available that can eliminate the adult worms ("macrofilaricide") using a short term treatment. Oxfendazole is a promising macrofilaricidal candidate with an improved oral availability in comparison to flubendazole and under preparation for phase 2 clinical trials in filariasis patients. Both benzimidazoles were tested in the Litomosoides sigmodontis mouse model, a model well established for preclinical drug development. Interestingly, several anti-filarial drugs require higher concentrations in vitro compared to in vivo to eliminate filariae. One possible reason for this discrepancy is that treatment efficacy of anti-filarial compounds is supported by the immune system.
Objectives
The aim of this study was to investigate the role of the immune system during treatment with two potential macrofilaricidal drugs, oxfendazole and flubendazole, and explore the potential to boost treatment efficacy via stimulation of the immune system.
Materials & Methods
Wildtype (WT) BALB/c, eosinophil-deficient dblGATA, IL-4R/IL-5-/-, antibody-deficient µMT and B, T and NK cell-deficient RAG2/IL-2Rγ-/- mice were infected with L. sigmodontis. Mice harbouring adult worms (35 dpi) were treated with an optimal and suboptimal dose of flubendazole (FBZ) or oxfendazole (OXF) for up to 5 days. In a second part, WT mice were treated for two to three days with a combination of a suboptimal dose of OXF and IL-4, IL-5 or IL-33.
Results
At 70 dpi, WT mice displayed a reduction of the mean adult worm burden by >94% compared to vehicle controls after both FBZ and OXF treatments. In contrast, treatment with either drug in knockout mice led to no reduction (RAG2/IL-2Rγ-/-) or a markedly lower reduction of the worm burden (dblGATA, IL-4R/IL-5-/-, µMT). The efficacy of a shortened treatment of OXF (-17.2% adult worms vs. vehicle) could be boosted to a 69.6% reduction via combination with IL-5, but not IL-4 or IL-33.
Conclusions
Our results suggest that various components of the immune system support the filaricidal effect of benzimidazoles in vivo and present an opportunity to boost treatment efficacy.