Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles
The model flatworm <i>Mesocestoides vogae</i> proliferating stage of infection elicits immunosuppression in the host. It was used to investigate the effects of human leukocyte extract (DLE) alone and in combination with anthelmintic albendazole (ABZ) on the reduction in peritoneal infect...
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MDPI AG
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| Online Access: | https://www.mdpi.com/1999-4923/15/2/541 |
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| author | Gabriela Hrčková Terézia Mačak Kubašková Dagmar Mudroňová Zuzana Jurčacková Denisa Ciglanová |
| author_facet | Gabriela Hrčková Terézia Mačak Kubašková Dagmar Mudroňová Zuzana Jurčacková Denisa Ciglanová |
| author_sort | Gabriela Hrčková |
| collection | DOAJ |
| description | The model flatworm <i>Mesocestoides vogae</i> proliferating stage of infection elicits immunosuppression in the host. It was used to investigate the effects of human leukocyte extract (DLE) alone and in combination with anthelmintic albendazole (ABZ) on the reduction in peritoneal infection, peritoneal exudate cells (PECs), their adherent counterparts, and peritoneal exudates after the termination of therapy. Balb/c mice were infected with the larvae of <i>M. vogae</i>. PECs and adherent macrophages were studied via flow cytometry, mRNA transcript levels, and immunofluorescence. The cytokine levels were measured via ELISA and larvae were counted. ABZ significantly reduced larval counts (581.2 ± 65, <i>p</i> < 0.001), but the highest reduction was observed after combined treatment with ABZ and DLE (389.2 ± 119, <i>p</i> < 0.001) in comparison with the control. Compared to an infected group, the proportions of CD11b+CD19- myeloid cells with suppressive ability decreased after albendazole (ABZ) in combination with DLE, which was the most effective in the elevation of B cells and CD11b+F4/80<sup>mid/high</sup>MHCII<sup>high</sup> macrophages/monocytes (22.2 ± 5.4%). Transcripts of the M2 macrophage markers (arginase 1, FIZZ-1, and Ym-1) were downregulated after DLE and combined therapy but not after ABZ, and the opposite trend was seen for iNOS. This contrasts with reduced ex vivo NO production by LPS-stimulated PECs from DLE and ABZ+DLE groups, where adherent macrophages/monocytes had elevated transcripts of the INF-γ receptor and STAT1 and reduced expression of STAT3, STAT6, and IL-10. Each therapy differentially modulated transcription profiles and concentrations of IFN-γ, TNF-α, IL-12p40, IL-6, IL-10, and TGF-β cytokines. DLE strongly ameliorated ABZ-induced suppression of INF-γ and IL-12 and preserved downregulation for IL-4, IL-10, and TGF-β. Epigenetic study on adherent macrophages from infected mice showed that ABZ, ABZ-sulfoxide, and DLE could interact with the mRNA of examined markers in a dose-dependent pattern. Co-administration of DLE with ABZ seemed to augment the drug’s larvicidal effect via modulation of immunity. In comparison with ABZ, combined therapy was the most effective in alleviating parasite-induced Th2/Treg/STAT3/STA6 directed immunosuppression by stimulating the Th1 cytokines, M1 macrophage polarization, and activation of the IFNγ/STAT1 signaling pathway. |
| first_indexed | 2024-03-11T08:17:17Z |
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| issn | 1999-4923 |
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| last_indexed | 2024-03-11T08:17:17Z |
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| spelling | doaj.art-c110d674c009458a8a79d389110c83a42023-11-16T22:41:19ZengMDPI AGPharmaceutics1999-49232023-02-0115254110.3390/pharmaceutics15020541Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine ProfilesGabriela Hrčková0Terézia Mačak Kubašková1Dagmar Mudroňová2Zuzana Jurčacková3Denisa Ciglanová4Institute of Parasitology, The Slovak Academy of Sciences, Hlinkova 3, 040 01 Košice, SlovakiaInstitute of Parasitology, The Slovak Academy of Sciences, Hlinkova 3, 040 01 Košice, SlovakiaDepartment of Microbiology and Immunology, University of Veterinary Medicine and Pharmacy, Komenského 68/73, 041 81 Košice, SlovakiaInstitute of Parasitology, The Slovak Academy of Sciences, Hlinkova 3, 040 01 Košice, SlovakiaInstitute of Parasitology, The Slovak Academy of Sciences, Hlinkova 3, 040 01 Košice, SlovakiaThe model flatworm <i>Mesocestoides vogae</i> proliferating stage of infection elicits immunosuppression in the host. It was used to investigate the effects of human leukocyte extract (DLE) alone and in combination with anthelmintic albendazole (ABZ) on the reduction in peritoneal infection, peritoneal exudate cells (PECs), their adherent counterparts, and peritoneal exudates after the termination of therapy. Balb/c mice were infected with the larvae of <i>M. vogae</i>. PECs and adherent macrophages were studied via flow cytometry, mRNA transcript levels, and immunofluorescence. The cytokine levels were measured via ELISA and larvae were counted. ABZ significantly reduced larval counts (581.2 ± 65, <i>p</i> < 0.001), but the highest reduction was observed after combined treatment with ABZ and DLE (389.2 ± 119, <i>p</i> < 0.001) in comparison with the control. Compared to an infected group, the proportions of CD11b+CD19- myeloid cells with suppressive ability decreased after albendazole (ABZ) in combination with DLE, which was the most effective in the elevation of B cells and CD11b+F4/80<sup>mid/high</sup>MHCII<sup>high</sup> macrophages/monocytes (22.2 ± 5.4%). Transcripts of the M2 macrophage markers (arginase 1, FIZZ-1, and Ym-1) were downregulated after DLE and combined therapy but not after ABZ, and the opposite trend was seen for iNOS. This contrasts with reduced ex vivo NO production by LPS-stimulated PECs from DLE and ABZ+DLE groups, where adherent macrophages/monocytes had elevated transcripts of the INF-γ receptor and STAT1 and reduced expression of STAT3, STAT6, and IL-10. Each therapy differentially modulated transcription profiles and concentrations of IFN-γ, TNF-α, IL-12p40, IL-6, IL-10, and TGF-β cytokines. DLE strongly ameliorated ABZ-induced suppression of INF-γ and IL-12 and preserved downregulation for IL-4, IL-10, and TGF-β. Epigenetic study on adherent macrophages from infected mice showed that ABZ, ABZ-sulfoxide, and DLE could interact with the mRNA of examined markers in a dose-dependent pattern. Co-administration of DLE with ABZ seemed to augment the drug’s larvicidal effect via modulation of immunity. In comparison with ABZ, combined therapy was the most effective in alleviating parasite-induced Th2/Treg/STAT3/STA6 directed immunosuppression by stimulating the Th1 cytokines, M1 macrophage polarization, and activation of the IFNγ/STAT1 signaling pathway.https://www.mdpi.com/1999-4923/15/2/541albendazoleDLEtreatmentcestode infectionmicemacrophages |
| spellingShingle | Gabriela Hrčková Terézia Mačak Kubašková Dagmar Mudroňová Zuzana Jurčacková Denisa Ciglanová Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles Pharmaceutics albendazole DLE treatment cestode infection mice macrophages |
| title | Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles |
| title_full | Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles |
| title_fullStr | Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles |
| title_full_unstemmed | Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles |
| title_short | Co-Treatment with Human Leukocyte Extract and Albendazole Stimulates Drug’s Efficacy and Th1 Biased Immune Response in <i>Mesocestoides vogae</i> (Cestoda) Infection via Modulation of Transcription Factors, Macrophage Polarization, and Cytokine Profiles |
| title_sort | co treatment with human leukocyte extract and albendazole stimulates drug s efficacy and th1 biased immune response in i mesocestoides vogae i cestoda infection via modulation of transcription factors macrophage polarization and cytokine profiles |
| topic | albendazole DLE treatment cestode infection mice macrophages |
| url | https://www.mdpi.com/1999-4923/15/2/541 |
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