Engagement of TLR signaling as adjuvant: towards smarter vaccine and beyond.

Neutrophil extracellular traps (NETs) have recently been discovered as a central part of antimicrobial innate immunity. In the meanwhile, evidence accumulated that NETs are also generated upon non-infectious stimuli in various clinical settings. In acute or chronic inflammatory disorders aberrantly enhanced NET formation and/or decreased NET degradation seems to correlate with disease outcome. This review summarizes current knowledge about the relation of NETs in a broad spectrum of clinical settings. Specifically, we focus on the importance of NETs as a predictive marker in severely ill patients and further, we speculate about the potential pathophysiology of NETs.

The clinical value of neutrophil extracellular traps

Objectives: Toll-like receptors (TLRs) are expressed in several immune cells including blood monocytes and resident macrophages, such as microglia in the central

Decreased Toll-Like Receptor 2 and Toll-Like Receptor 7/8-Induced Cytokines in Parkinson's Disease Patients.

IL-27 regulates immune responses as well as hematopoiesis and bone remodeling, but its cellular sources in the bone remain unknown. In this study, we investigated whether osteoclasts and osteoblasts-the 2 cell types orchestrating bone homeostasis-could be a source of IL-27 and identified stimuli that induce its expression in vitro. We observed that human monocyte-derived osteoclasts expressed a broader range of TLRs than did human primary osteoblasts and that both cell types exhibited a differential induction of IL-27 expression in response to TLR or cytokine stimulation. Whereas several TLR agonists, notably TLR4 and TLR7/8 agonists, induced substantial expression of IL-27 by osteoclasts, stimulation of osteoblasts with agonists of TLR3 and/or TLR4-the 2 TLRs selectively expressed by these cells-resulted in no or low IL-27 expression. In addition, IL-27 increased TLR3 expression in osteoclasts and enhanced poly(I:C)-mediated induction of IL-27 in these cells. IFN-γ, when combined with either IL-1β plus TNF-α, IL-11, or CNTF, induced significant levels of IL-27 in osteoclasts but not in osteoblasts. In the latter cells, the addition of type I IFN, together with proinflammatory cytokines, was necessary to induce substantial levels of IL-27. Immunohistochemical studies of inflamed and remodeling bone tissue, including cases of infectious osteomyelitis and bone metastases, provided evidence that osteoclasts, osteoblasts, and occasionally osteocytes or chondrocytes, could express IL-27 in situ. This autocrine production of IL-27 by TLR- or cytokine-activated bone cells might constitute a negative-feedback mechanism to limit bone erosion and to dampen T cell-mediated immune pathology during bone inflammation.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.3HI0616-280R

Frontline Science: Human bone cells as a source of IL-27 under inflammatory conditions: role of TLRs and cytokines.

Haemophilus influenzae type b (Hib) and 7-valent pneumococcal (PCV7) vaccines both became recommended in Japan in 2010. In this study, cytokine production was investigated in peripheral blood mononuclear cells (PBMCs) cultures stimulated with diphtheria and tetanus toxoids combined with acellular pertussis vaccine (DPT), Hib, and PCV7 separately or concurrent different combinations, all as final off-the-shelf vaccines without the individual vaccine components as controls. Higher IL-1β levels were produced when cultures were stimulated with PCV than with DPT or Hib, and the concurrent stimulation including PCV7 enhanced the production of IL-1β. Although Hib induced higher levels of IL-6, no significant difference was observed in IL-6 production with the concurrent stimulation. The concurrent stimulation with Hib/PCV7 and DPT/Hib/PCV7 produced higher levels of TNF-α and human G-CSF. Cytokine profiles were examined in serum samples obtained from 61 vaccine recipients with febrile reactions and 18 recipients without febrile illness within 24 h of vaccination. No significant difference was observed in cytokine levels of IL-1β, IL-4, IL-6, IL-10, IL-12, IFN-γ, MIP-1, TNF-α, and prostaglandin E2 (PGE2) in sera between the two groups. However, significantly higher levels of human G-CSF were observed in recipients with febrile illness than in those without febrile reactions. Further investigations of the significance of elevated serum G-CSF levels are required in vaccine recipients with febrile illness.

Production of inflammatory cytokines in response to diphtheria-pertussis-tetanus (DPT), haemophilus influenzae type b (Hib), and 7-valent pneumococcal (PCV7) vaccines

We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human Toll-like receptor molecules in vitro Using P3CSK4, Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFNγ+/CD4+ T cells from their naive precursors following priming with allogeneic DC in vitro In contrast, co-culture of naive CD4+ T cells with allogeneic monocytes and TLR2/TLR4 agonists only resulted in enhanced T cell proliferation Distinct APC molecular signatures in response to each TLR agonist underline the dual effect observed on T cell responses Using protein and gene expression assays, we show that TNF-α and CXCL10 represent DC-restricted molecular signatures of TLR2/TLR4 and TLR3 activation, respectively, in sharp contrast to IL-6 produced by monocytes upon stimulation with P3CSK4 and Lipid A Furthermore, although all TLR agonists are able to up-regulate proIL-1β specific gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1β release These molecular profiles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application

/pdf/using-distinct-molecular-signatures-of-human-monocytes-and-56nyjf06wk.pdf

Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists

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Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists