Targeting of Immune Cells by Dual TLR2/7 Ligands Suppresses Features of Allergic Th2 Immune Responses in Mice

Laiño, Jonathan Emiliano; Wangorsch, Andrea; Blanco, F. López; Wolfheimer, Sonja; Krause, Maren; Flaczyk, Adam; Möller, Tobias Maximilian; Tsai, Mindy; Galli, Stephen J.; Vieths, Stefan; Toda, Masako; Scheurer, Stephan; Schülke, Stefan

doi:10.1155/2017/7983217

Cited by 12 publications

(13 citation statements)

References 32 publications

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“…In preclinical studies, much higher doses of CpG ODN (2.5 mg/kg) were administered daily to mice while 4 μg/ml of CpG-A or CpG-B were used in our experiments 48 . Also the dose of CL413 agonist (5 μg/ml) was within the range of the dose administered to mice in preclinical studies (3 μg/g) 49 . Further studies of the distinct antiviral potential of poly-specific TLR agonists are necessary to elucidate their functions, which could provide new opportunities for the development of novel strategies to achieve sustained viral clearance and provide a definitive cure for hepatitis B.…”

Section: Discussionmentioning

confidence: 84%

Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

Janovec

Hodek

Clarova

et al. 2020

Sci Rep

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Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.

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Section: Discussionmentioning

confidence: 84%

Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

Janovec

Hodek

Clarova

et al. 2020

Sci Rep

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“…Here, chemical conjugation of the TLR2-ligand Pam 3 CysK 4 to OVA-derived CD8 + T cell peptide sequences resulted in a rapid and enhanced uptake in DCs ( 119 ). Moreover, dual TLR2/7-ligands combining the TLR2-ligand Pam 2 CysK 4 and the synthetic TLR7-ligand CL264 into a single molecule were shown to induce strongly activated mDCs co-producing IL-10 and pro-inflammatory IL-6 (Figure 3 A) ( 88 ). In vitro , these mDCs suppressed both DNP-induced, IgE- and Ag-dependent mast cell degranulation and IL-5 secretion from OVA-specific DO11.10 CD4 + TC (Figure 3 B) ( 88 ).…”

Section: Strategies To Induce Dc-derived Il-10 Secretionmentioning

confidence: 99%

“…Moreover, dual TLR2/7-ligands combining the TLR2-ligand Pam 2 CysK 4 and the synthetic TLR7-ligand CL264 into a single molecule were shown to induce strongly activated mDCs co-producing IL-10 and pro-inflammatory IL-6 (Figure 3 A) ( 88 ). In vitro , these mDCs suppressed both DNP-induced, IgE- and Ag-dependent mast cell degranulation and IL-5 secretion from OVA-specific DO11.10 CD4 + TC (Figure 3 B) ( 88 ). In vivo application of one of these ligands, CL531, was found to suppress allergen-specific IgE production in a mouse model of OVA-induced intestinal allergy, suggesting that such TLR2/7-ligands have the potential to induce Th1-biased immune modulation in vivo ( 88 ).…”

Section: Strategies To Induce Dc-derived Il-10 Secretionmentioning

confidence: 99%

“…In vitro , these mDCs suppressed both DNP-induced, IgE- and Ag-dependent mast cell degranulation and IL-5 secretion from OVA-specific DO11.10 CD4 + TC (Figure 3 B) ( 88 ). In vivo application of one of these ligands, CL531, was found to suppress allergen-specific IgE production in a mouse model of OVA-induced intestinal allergy, suggesting that such TLR2/7-ligands have the potential to induce Th1-biased immune modulation in vivo ( 88 ).…”

Section: Strategies To Induce Dc-derived Il-10 Secretionmentioning

confidence: 99%

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Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

2018

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Dendritic cells (DCs) are gatekeepers of the immune system that control induction and polarization of primary, antigen-specific immune responses. Depending on their maturation/activation status, the molecules expressed on their surface, and the cytokines produced DCs have been shown to either elicit immune responses through activation of effector T cells or induce tolerance through induction of either T cell anergy, regulatory T cells, or production of regulatory cytokines. Among the cytokines produced by tolerogenic DCs, interleukin 10 (IL-10) is a key regulatory cytokine limiting und ultimately terminating excessive T-cell responses to microbial pathogens to prevent chronic inflammation and tissue damage. Because of their important role in preventing autoimmune diseases, transplant rejection, allergic reactions, or in controlling chronic inflammation DCs have become an interesting tool to modulate antigen-specific immune responses. For the treatment of allergic inflammation, the aim is to downregulate allergen-specific T helper 2 (Th2) responses and the associated clinical symptoms [allergen-driven Th2 activation, Th2-driven immunoglobulin E (IgE) production, IgE-mediated mast cell and basophil activation, allergic inflammation]. Here, combining the presentation of allergens by DCs with a pro-tolerogenic, IL-10-producing phenotype is of special interest to modulate allergen-specific immune responses in the treatment of allergic diseases. This review discusses the reported strategies to induce DC-derived IL-10 secretion for the suppression of allergen-specific Th2-responses with a focus on IL-10 treatment, IL-10 transduction, and the usage of both whole bacteria and bacteria-derived components. Interestingly, while IL-10-producing DCs induced either by IL-10 treatment or IL-10 transduction are arrested in an immature/semi-mature state, treatment of DCs with live or killed bacteria as well as isolated bacterial components results in the induction of both anti-inflammatory IL-10 and pro-inflammatory, Th1-promoting IL-12 secretion often paralleled by an enhanced expression of co-stimulatory molecules on the stimulated DCs. By the secretion of DC-derived exosomes or CC-chemokine ligand 18, as well as the expression of inhibitory molecules like cytotoxic T lymphocyte-associated antigen 4, TNF receptor superfamily member 4, Ig-like transcript-22/cluster of differentiation 85, or programmed death-1, IL-10-producing DCs have been repeatedly shown to suppress antigen-specific Th2-responses. Therefore, DC-based vaccination approaches hold great potential to improve the treatment of allergic diseases.

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“…For example, TLR-2 activation led to the production of TNF, IL-6, IL-13, IL-4, and IL-5, while TLR-4 induced TNF, IL-6, IL-13, and IL-1b ( 88 ). Interestingly, pre-exposure to TLR ligands suppressed IgE-induced mast cell responses in two mouse models, possibly by transiently reducing FcεRI expression ( 89 , 90 ). By contrast, simultaneous exposure of human mast cells to various TLR ligands and FcεRI stimulation yielded increased cytokine secretion without altering degranulation ( 91 ).…”

Section: Activating Ligands and Receptors Regulating Mast Cell Functimentioning

confidence: 99%

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

et al. 2018

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Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area.

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Targeting of Immune Cells by Dual TLR2/7 Ligands Suppresses Features of Allergic Th2 Immune Responses in Mice

Cited by 12 publications

References 32 publications

Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes

Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

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