The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4

Mata-Haro, Verónica; Cekic, Caglar; Martin, Michael; Chilton, Paula M.; Casella, Carolyn R.; Mitchell, Thomas C.

doi:10.1126/science.1138963

Cited by 780 publications

(807 citation statements)

References 26 publications

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“…On the other hand, the blunted response of TRIF-deficient BMDC to diC14 amidine demonstrates that the action of these cationic liposomes also depends on TRIF signaling. This is consistent with the up-regulation of the expression of costimulatory molecules and the induction of IFN-b and CXCL-10 gene transcription induced by diC14 amidine in human DC since both phenomena were shown to require TRIF signaling [18,20,21].…”

Section: Stimulation Of DC By Dic14-amidine Liposomes Depends On Tlr4supporting

confidence: 84%

“…Molecular dynamics simulations of the insertion of diC14-anidine in MD2 cavity revealed that two amidine molecules do occupy a volume identical to that of one tetra-acylated lipid A molecule in the cavity (M. Lensink, personal communication) Indeed, our findings might lead to the development of diC14-amidine as a vaccine adjuvant since there is growing interest in the use of TLR4 ligands to induce T cell-mediated immunity. Interestingly, monophosphoryl lipid A, which is the TLR4 ligand in the most advanced phase of clinical development, was recently shown to be rather inefficient in inducing MyD88-dependent responses, whereas it elicits MyD88-independent TRIF-dependent cytokine production [18]. Since it has been shown that MyD88-mediated signaling is required for the induction of Th1-type immune responses [19], activation of the MyD88-dependent pathway might be required for adjuvants included in vaccines against intracellular pathogens or tumors and in anti-allergy immunotherapies.…”

Section: Stimulation Of DC By Dic14-amidine Liposomes Depends On Tlr4mentioning

confidence: 99%

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DiC14‐amidine cationic liposomes stimulate myeloid dendritic cells through Toll‐like receptor 4

et al. 2008

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DiC14-amidine cationic liposomes were recently shown to promote Th1 responses when mixed with allergen. To further define the mode of action of diC14-amidine as potential vaccine adjuvant, we characterized its effects on mouse and human myeloid dendritic cells (DC). First, we observed that, as compared with two other cationic liposomes, only diC14-amidine liposomes induced the production of IL-12p40 and TNF-a by mouse bone marrowderived DC. DiC14-amidine liposomes also activated human DC, as shown by synthesis of IL-12p40 and TNF-a, accumulation of IL-6, IFN-b and CXCL10 mRNA, and up-regulation of membrane expression of CD80 and CD86. DC stimulation by diC14-amidine liposomes was associated with activation of NF-jB, ERK1/2, JNK and p38 MAP kinases. Finally, we demonstrated in mouse and human cells that diC14-amidine liposomes use Toll-like receptor 4 to elicit both MyD88-dependent and Toll/IL-1R-containing adaptor inducing interferon IFN-b (TRIF)-dependent responses.

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Section: Stimulation Of DC By Dic14-amidine Liposomes Depends On Tlr4supporting

confidence: 84%

Section: Stimulation Of DC By Dic14-amidine Liposomes Depends On Tlr4mentioning

confidence: 99%

DiC14‐amidine cationic liposomes stimulate myeloid dendritic cells through Toll‐like receptor 4

et al. 2008

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“…Fourth, different transcription factors or intracellular signaling molecules might be involved in S100A8 and SAA3 signaling. For example, both lipid A and monophosphoryl lipid A bind the TLR4/MD-2 complex but monophosphoryl lipid A selectively activates only the Toll-like Interleukin 1 Receptor domain-containing adaptor-inducing interferon-b (TRIF)-TRIF-related adaptor molecule (TRAM) but not the nuclear factorkB pathway (Mata-Haro et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

et al. 2011

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We have previously shown that tumor necrosis factor (TNF)a produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b þ TLR4 þ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4 þ Clara cells could be derived from bone marrow. SAA3-induced TNFa expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNFa in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin.

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“…21,[32][33][34][35][36][37] It was not until 2007 that the basis of the dissociation between toxicity of diphosphoryl lipid A (DPLA) on the one hand, and the potent adjuvanticity (and nontoxicity) of monophosphoryl lipid A (MPLA), on the other, became apparent. 38 Whereas DPLA, upon binding to TLR4, signals via both myeloid differentiation factor 88 (MyD88) as well as Toll-interleukin 1 receptor domain-containing adapter inducing interferon-β (TRIF)-dependent pathways, 14,[39][40][41][42][43][44][45] MPLA appears to predominantly trigger the TRIF-dependent pathway. 38 In the case of the LPS receptor TLR4, it is MyD88 that is associated with proinflammatory outcomes, while activation of TRIF-dependent pathways are correlated with immunostimulation.…”

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confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4

Cited by 780 publications

References 26 publications

DiC14‐amidine cationic liposomes stimulate myeloid dendritic cells through Toll‐like receptor 4

DiC14‐amidine cationic liposomes stimulate myeloid dendritic cells through Toll‐like receptor 4

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

Potential adjuvantic properties of innate immune stimuli

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