The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-γ–producing cells

Brugnolo, Francesca; Liotta, Francesco; Cosmi, Lorenzo; Annunziato, Francesco; Manuelli, Cinzia; Campi, Paolo; Maggi, Enrico; Romagnani, Sergio; Parronchi, Paola

doi:10.1067/mai.2003.102

Cited by 86 publications

(64 citation statements)

References 28 publications

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“…R-848 is a synthetic agonist for TLR7 and TLR8 and is easily usable in in vitro assays. In the presence of APCs, R-848 shifts human allergen-specific CD4 ϩ Th2 lymphocytes into IFN-␥-producing cells (42). Our study shows a direct effect of R-848 on IFN-␥ production by human T cells with no induction of IL-4 or Th2-attracting chemokines (data not shown).…”

Section: Discussionmentioning

confidence: 62%

Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells

Caron

Duluc

Frémaux

et al. 2005

The Journal of Immunology

375

349

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TLRs are involved in innate cell activation by conserved structures expressed by microorganisms. Human T cells express the mRNA encoding most of TLRs. Therefore, we tested whether some TLR ligands may modulate the function of highly purified human CD4+ T lymphocytes. We report that, in the absence of APCs, flagellin (a TLR5 ligand) and R-848 (a TLR7/8 ligand) synergized with suboptimal concentrations of TCR-dependent (anti-CD3 mAb) or -independent stimuli (anti-CD2 mAbs or IL-2) to up-regulate proliferation and IFN-γ, IL-8, and IL-10 but not IL-4 production by human CD4+ T cells. No effect of poly(I:C) and LPS, ligands for TLR3 and TLR4, respectively, was detected. We also observed that CD4+CD45RO+ memory T cell responses to TLR ligands were more potent than those observed with CD4+CD45RA+ naive T cells. Moreover, among the memory T cells, CCR7− effector cells were more sensitive to TLR ligands than CCR7+ central memory cells. These data demonstrate for the first time a direct effect of TLR5 and TLR7/8 ligands on human T cells, and highlight an innate arm in T cell functions. They also suggest that some components from invading microorganisms may directly stimulate effector memory T cells located in tissues by up-regulating cytokine and chemokine production.

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Section: Discussionmentioning

confidence: 62%

Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells

Caron

Duluc

Frémaux

et al. 2005

The Journal of Immunology

375

349

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“…We have also observed that R-848 did not induce degranulation and IL-13 production by FSMC. Recent observations have indicated that R-848 inhibited IgE production by peripheral mononuclear cells derived from nonallergic and allergic donors (78), and shifted allergen-specific CD4 ϩ Th2 lymphocytes into IFN-␥-producing Th1 cells (79). These findings suggest that imidazoquinoline compounds may modulate immunity from Th2 to Th1 responses.…”

Section: Discussionmentioning

confidence: 70%

TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells

Matsushima

Yamada

Matsue

et al. 2004

The Journal of Immunology

241

224

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Recent studies have revealed that murine bone marrow-derived cultured mast cells (BMMC), which are phenotypically immature mast cells, express functional TLR2 and TLR4 that recognize distinct pathogen-associated molecules. However, it remains relatively uncertain whether mast cells express other TLR. We recently established a method to obtain large numbers of murine fetal skin-derived cultured mast cells (FSMC); these cells exhibit important features of connective tissue type mast cells. Working with FSMC and BMMC, the TLR mRNA expression profiles were compared between both cell types. Although TLR2 and TLR4 mRNA were detected in both cells at comparable levels, TLR3, TLR7, and TLR9 mRNA were expressed by FSMC at higher levels than by BMMC, suggesting distinct TLR expression profiles among different mast cell populations. With respect to their functional aspects, FSMC, but not BMMC, dose dependently produced proinflammatory cytokines (TNF-α and IL-6) and chemokines (RANTES, MIP-1α, and MIP-2) in response to poly(I:C), R-848, and CpG oligodeoxynucleotide, which are TLR3, TLR7, and TLR9 activators, respectively. Interestingly, these TLR activators failed to induce degranulation and IL-13 production by both mast cells, although peptidoglycan and LPS (TLR2 and TLR4 activators, respectively) induced IL-13 production by both cells. Mast cells, thus, may have potential to recruit other immune cells to the infected sites by responding to various bacterial and viral components through TLR signaling pathways, presumably being involved in initiating innate immunity and subsequently linking innate and acquired immune responses.

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“…Allergen-specific T-cell lines (TCLs) from PBMCs of 10 atopic donors and CD4 1 CRTH2 1 T cells of 4 atopic donors were generated in the presence of nDer p 2 or nDer p 2-Conj (10 mg/mL), as previously described 18 and specified in the Methods section in this article's Online Repository.…”

Section: Generation Of Antigen-specific Short-term T-cell Lines and Tmentioning

confidence: 99%

“…16,18 The functional phenotype of T-cell blasts was analyzed as described in the Methods section in this article's Online Repository.…”

Section: Generation Of Antigen-specific Short-term T-cell Lines and Tmentioning

confidence: 99%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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The novel synthetic immune response modifier R-848 (Resiquimod) shifts human allergen-specific CD4+ TH2 lymphocytes into IFN-γ–producing cells

Cited by 86 publications

References 28 publications

Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells

Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-γ Production by Memory CD4+ T Cells

TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

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