A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses

Jackson, David C.; Lau, Yuk Fai; Le, Thuy T.; Suhrbier, Andreas; Deliyannis, Georgia; Cheers, Christina; Smith, Corey; Zeng, Weiguang; Brown, Lorena E.

doi:10.1073/pnas.0406740101

Cited by 231 publications

(225 citation statements)

References 42 publications

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“…First, TLRs trigger the secretion of critical cytokines such as IL1, IL-6 and IL-12 by DCs, which are important for T-cell differentiation and the induction of potent adaptive immunity. Several groups have shown that conjugation of certain TLR ligands (that is, for TLR2, TLR4, TLR7 and TLR9) to peptides or proteins significantly enhances CD4 þ and CD8 þ T-cell responses compared with administration of TLR ligands or a peptide/protein mixture alone (Jackson et al, 2004;Wille-Reece et al, 2005;Blander and Medzhitov, 2006). Third, TLRs can directly stimulate the proliferation of CD4 þ and CD8 þ T cells as well as reverse the suppressive function of Treg cells (Crellin et al, 2005;Peng et al, 2005;Tabiasco et al, 2006).…”

Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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“…Several other molecules like the scavenger receptor Lox-1 (11), the mannose receptor (12), some chemokine receptors (13,14), and TLRs (15,16) have been tested for their potential in immunotherapy. A critical lesson from all of these studies is that some receptors (4,5,11,12), but not others (16,17), require the addition of a DC maturation signal to induce protective immunity. Collectively, it is difficult to predict which strategy among the proposed ones is the most efficient on a comparative basis.…”

Section: Selection Of An Antibody Library Identifies a Pathway Tomentioning

confidence: 99%

Selection of an Antibody Library Identifies a Pathway to Induce Immunity by Targeting CD36 on Steady-State CD8α+ Dendritic Cells

Tagliani

Guermonprez

Sepúlveda

et al. 2008

The Journal of Immunology

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Improvement of the strategy to target tumor Ags to dendritic cells (DCs) for immunotherapy requires the identification of the most appropriate ligand/receptor pairing. We screened a library of Ab fragments on mouse DCs to isolate new potential Abs capable of inducing protective immune responses. The screening identified a high-affinity Ab against CD36, a multi-ligand scavenger receptor primarily expressed by the CD8α+ subset of conventional DCs. The Ab variable regions were genetically linked to the model Ag OVA and tested in Ag presentation assays in vitro and in vivo. Anti-CD36-OVA was capable of delivering exogenous Ags to the MHC class I and MHC class II processing pathways. In vivo, immunization with anti-CD36-OVA induced robust activation of naive CD4+ and CD8+ Ag-specific T lymphocytes and the differentiation of primed CD8+ T cells into long-term effector CTLs. Vaccination with anti-CD36-OVA elicited humoral and cell-mediated protection from the growth of an Ag-specific tumor. Notably, the relative efficacy of targeting CD11c/CD8α+ via CD36 or DEC205 was qualitatively different. Anti-DEC205-OVA was more efficient than anti-CD36-OVA in inducing early events of naive CD8+ T cell activation. In contrast, long-term persistence of effector CTLs was stronger following immunization with anti-CD36-OVA and did not require the addition of exogenous maturation stimuli. The results identify CD36 as a novel potential target for immunotherapy and indicate that the outcome of the immune responses vary by targeting different receptors on CD8α+ DCs.

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“…The conjugation of a vaccine Ag to a TLR2 agonist was shown to increase both Ab and T cell responses, and thus, TLR2 agonists can clearly function as adjuvants (21). In addition, vaccines against yellow fever and against Pneumococcus have been shown to be efficient partly due to associated TLR2 agonists (17,22).…”

Section: Discussionmentioning

confidence: 99%

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Gallorini

Parente

Baronio

et al. 2007

The Journal of Immunology

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It was shown previously that bacterial polysaccharides (PS), which naturally contain both positive and negative charges, are able to activate T cells and APCs. However, the vast majority of bacterial PS are anionic and do not have these properties. In this study, we show that chemical introduction of positive charges into naturally anionic bacterial PS confers to the resulting zwitterionic PS (ZPS) the ability to activate pure human monocytes, monocyte-derived dendritic cells, and mouse bone marrow-derived dendritic cells, as do natural bacterial ZPS. Cells are induced to up-regulate MHC class II and costimulatory molecules and to produce cytokines. In mixed monocyte-T cell cocultures, ZPS induce MHC II-dependent T cell proliferation and up-regulation of activation markers. These stimulatory qualities of ZPS disappear when the positive charge is chemically removed from the molecules and thus the zwitterionic motif is destroyed. The ability of natural and chemically derived ZPS to activate APCs can be blocked by anti-TLR2 mAbs, and TLR2 transfectants show reporter gene transcription upon incubation with ZPS. In conclusion, the generation of a zwitterionic motif in bacterial PS confers the ability to activate both APCs and T cells. This finding has important implications for the design of novel polysaccharide vaccines.

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A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses

Cited by 231 publications

References 42 publications

Toll-like receptors and immune regulation: implications for cancer therapy

Toll-like receptors and immune regulation: implications for cancer therapy

Selection of an Antibody Library Identifies a Pathway to Induce Immunity by Targeting CD36 on Steady-State CD8α+ Dendritic Cells

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

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