Contents lists available at ScienceDirect Experimental Parasitology journal homepage: www.elsevier.com/locate/yexpr Co-administration of silymarin elevates the therapeutic effect of praziquantel through modulation of specific antibody profiles, Th1/Th2/ Tregs cytokines and down-regulation of fibrogenesis in mice with Mesocestoides vogae (Cestoda) infection Gabriela Hrčková a,* , Terézia Mačák Kubašková a , Katarína Reiterová a , David Biedermann b a Institute of Parasitology of the Slovak Academy of Sciences, Hlinkova 3, 04001, Košice, Slovak Republic b Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 14220, Prague, Czech Republic ARTICLE INFO Keywords: Mesocestoides vogae Praziquantel Silymarin Immunity Fibrosis Parasite counts ABSTRACT Silymarin (SIL) represents a natural mixture of polyphenols showing an array of health benefits. The present study, carried out on a model cestode infection induced by Mesocestoides vogae tetrathyridia in the ICR strain of mice, was aimed at investigating the impact of SIL as adjunct therapy on the activity of praziquantel (PZQ) in relation to parasite burden, immunity and liver fibrosis within 20 days post-therapy. In comparison with PZQ alone, co-administration of SIL and PZQ stimulated production of total IgG antibodies to somatic and excretory- secretory antigens of metacestodes and modified the expression patterns of immunogenic molecules in both antigenic preparations. The combined therapy resulted in the elevation of IFN-γ and a decline of TNF-α and TGF- β1 in serum as compared to untreated group; however, SIL attenuated significantly the effect of PZQ on IL-4 and stimulated PZQ-suppressed phagocytosis of peritoneal macrophages. In the liver, SIL boosted the effect of PZQ on gene expression of the same cytokines in a similar way as was found in serum, except for down-regulation of PZQ-stimulated TNF-α. Compared to PZQ therapy, the infiltration of mast cells into liver after SIL co-adminis- tration was nearly abolished and correlated with suppressed activities of genes for collagen I, collagen III and α- SMA. In conclusion, co-administration of SIL modified the effects of PZQ therapy on antigenic stimulation of the immune system and modulated Th1/Th2/Tregs cytokines. In liver this was accompanied by reduced fibrosis, which correlated with significantly higher reduction of total numbers of tetrathyridia after combined therapy as compared with PZQ treatment. 1. Introduction The metacestodes of several medically important cestode parasites invade various tissues and cavities of their vertebrate hosts, where they can grow asexually, causing severe pathology. The metacestode stage (tetrathyridium) of the cestode Mesocestoides (M.) vogae (syn. M. corti) multiplies asexually in the liver and in the peritoneal cavity of rodents. Due to the close genetic and immunological relationship to cestodes of medical relevance, such as those from the Echinococcus and Taenia genera, the M. vogae – mouse model has been proposed as a suitable in vitro-in vivo model in pharmacological studies (Eckert et al., 1984). A common feature of these infections is the Th2-biased immune response that develops after suppression of the initial Th-1 response, leading to the establishment of infections. The chronicity and reduced pathology is associated with induction of T regulatory cells (CD4 + CD25+Foxp3+), which are potent suppressor cells of the adaptive immune system, producing TGF-β and IL-10 cytokines (Maizels and Yazdanbakhsh, 2003). Parasite-derived excretory/secre- tory (ES) products have an essential role in this process (Grainger et al., 2010) as well as in the shift towards Th2 type of immunity on the local and systemic levels, involving cytokines IL-4, IL-13, IL-5 and IL-9 (Hewitson et al., 2009). The migration of M. vogae tetrathyridia within the liver causes se- vere damage to parenchymal tissue, resulting in the development of fibrosis (Riley and Chernin, 1994; Hrčková et al., 2010). In M. vogae infection, the early shift from Th1 to Th2 immunity in the spleen and peritoneal cavity of mice was observed from day 7 post-infection on- wards. Moreover, we showed that metacestode-derived ES antigens elicited the massive accumulation of myeloid-derived cells and alter- natively activated macrophages with immunosuppressive https://doi.org/10.1016/j.exppara.2020.107888 Received 24 June 2019; Received in revised form 9 January 2020; Accepted 22 March 2020 * Corresponding author. E-mail address: hrcka@saske.sk (G. Hrčková). Experimental Parasitology 213 (2020) 107888 Available online 04 April 2020 0014-4894/ © 2020 Elsevier Inc. All rights reserved. T