Cl097, a Tlr7/8 Ligand, Inhibits TLR-4-Dependent Activation of Irak-M and BCL-3 Expression

Petričević, Branka; Wessner, Barbara; Sachet, Monika; Vrbanec, Damir; Spittler, Andreas; Bergmann, Michael

doi:10.1097/shk.0b013e3181a5ac8a

Cited by 19 publications

(12 citation statements)

References 28 publications

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“…This increased pattern was sustained for more than 6 hours of treatment, which was similar to TLRs 7 and 8 but in the opposite direction. According to Petricevic et al20 TLR 4 expression decreases in response to TLRs 7 and 8 ligand-activating treatment. Collectively, these results suggest a complex interaction between these ligands.…”

Section: Discussionmentioning

confidence: 99%

The Expression of Toll-Like Receptors (TLRs) in Cultured Human Skin Fibroblast is Modulated by Histamine

et al. 2012

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Fibroblasts are responsible for the synthesis and degradation of various connective tissue components and soluble mediators of extracellular matrix metabolism. Few studies have been conducted concerning the expression of toll-like receptors (TLRs) in fibroblasts until now. This study aimed first to determine the quantitative expression of TLRs 1 to 10 in human skin fibroblasts and secondarily to explore any influence of expression by histamine, which is a well-known factor engaged in dermal inflammation. It was found that all 10 TLRs were expressed in fibroblasts. Interestingly, the expression of TLRs 4, 5, and 10 was increased after 2 and 6 hours of histamine treatment during culture. However, the expression of TLRs 2, 3, 6, 7, 8, and 9 was decreased after 6 hours of histamine treatment. Among the TLRs with a decreasing expression pattern, TLRs 7 and 8 showed a persistent tendency to decrease. All of these changes in TLR expression with histamine treatment were antagonized by treatment with diphenhydramine, a well-known antihistamine. Thus, these results suggest a role of histamine in the early phase of the dermal inflammatory reaction mediated by TLRs.

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Section: Discussionmentioning

confidence: 99%

The Expression of Toll-Like Receptors (TLRs) in Cultured Human Skin Fibroblast is Modulated by Histamine

et al. 2012

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“…In this study we chose to investigate potential adjuvant effects of a combination of the synthetic monophosphoryl lipid A (MPLA) based TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA), that acts in a TRIF pathway biased manner [ 5 – 7 ] and resiquimod (R848), a TLR7/8 agonist acting through MyD88 dependent signalling [ 4 ]. A number of previous in vitro studies using human APC, and in particular monocyte-derived macrophages and dendritic cells, have demonstrated synergy between TLR4 and TLR7/8 stimulation with enhanced cytokine production, reciprocal upregulation of each receptor [ 8 , 9 ], and enhanced potential for activation of T-helper cell type 1 and/ or 17 responses [ 10 – 12 ]. The latter is effective in providing B cell help, promoting antibody production and class switch recombination [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

TLR4 and TLR7/8 Adjuvant Combinations Generate Different Vaccine Antigen-Specific Immune Outcomes in Minipigs when Administered via the ID or IN Routes

et al. 2016

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The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models.

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“…In this way, developers have a better chance of avoiding combinations that may have antagonistic, rather than additive or synergistic effects on immune responses (74). Similarly, the possible effects of combinations that synergistically induce remarkably high levels of inflammatory mediators in preclinical models, such as TNFα, IL-lβ, IL-12 and IFNγ (75;76), and may pose a potential risk for local and/or systemic inflammation.…”

Section: Combination Adjuvants For Cancer Vaccinesmentioning

confidence: 99%

Current challenges for cancer vaccine adjuvant development

Bowen

Svrivastava

Batra

et al. 2018

Expert Review of Vaccines

122

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Introduction: Although much progress has been made in the last decade(s) toward development of effective cancer vaccines, there are still important obstacles to therapeutic successes. New generations of cancer vaccines will benefit from a combination adjuvant approach that targets multiple branches of the immune response. Areas covered: Herein we describe how combinatorial adjuvant strategies can help overcome important obstacles to cancer vaccine development, including antigen immunogenicity and tumor immune suppression. Tumor antigens may be both tolerogenic and may utilize active mechanisms to suppress host immunity, including downregulation of MHC molecules to evade recognition and upregulation of immune inhibitory receptors, to subvert an effective immune response. The current cancer vaccine literature was surveyed to identify advancements in the understanding of the biological mechanisms underlying poor antigen immunogenicity and tumor immune evasion, as well as adjuvant strategies designed to overcome them. Expert commentary: Poor immunogenicity of tumor antigens and tumor immune evasion mechanisms make the design of cancer vaccines challenging. Growing understanding of the tumor microenvironment and associated immune responses indicate the importance of augmenting not only the effector response, but also overcoming the endogenous regulatory response and tumor evasion mechanisms. Therefore, new vaccines will benefit from multi-juvanted approaches that simultaneously stimulate immunity while preventing inhibition.

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Cl097, a Tlr7/8 Ligand, Inhibits TLR-4-Dependent Activation of Irak-M and BCL-3 Expression

Cited by 19 publications

References 28 publications

The Expression of Toll-Like Receptors (TLRs) in Cultured Human Skin Fibroblast is Modulated by Histamine

The Expression of Toll-Like Receptors (TLRs) in Cultured Human Skin Fibroblast is Modulated by Histamine

TLR4 and TLR7/8 Adjuvant Combinations Generate Different Vaccine Antigen-Specific Immune Outcomes in Minipigs when Administered via the ID or IN Routes

Current challenges for cancer vaccine adjuvant development

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