Enhancement of antigen-specific immunity via the TLR4 ligands MPL™ adjuvant and Ribi.529

Evans, John K.; Cluff, C W; Johnson, David A.; Lacy, Michael J.; Persing, David H.; Baldridge, Jory R.

doi:10.1586/14760584.2.2.219

Cited by 227 publications

(142 citation statements)

References 14 publications

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“…However, in striking contrast, the adjuvant effect of Ribi, an unrelated TLR4 ligand, monophosphoryl lipid A-dominated adjuvant, gave anti-NP IgG1 responses that were comparable to those seen in WT mice (Fig. 6G) (49). Thus, Cr2 2/2 mice demonstrated a selective defect in the adjuvant function of CTA1-DD, whereas the enhancing effect of Ribi was intact in these mice, indicating that CTA1-DD, as opposed to Ribi, was dependent on complement and complement receptor expression.…”

Section: Localization Of Cta-dd Adjuvant To the Fdc Is Dependent On Cmentioning

confidence: 78%

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Mattsson

Stensson

Schön

et al. 2011

The Journal of Immunology

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A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2−/− mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2−/− mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.

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Section: Localization Of Cta-dd Adjuvant To the Fdc Is Dependent On Cmentioning

confidence: 78%

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Mattsson

Stensson

Schön

et al. 2011

The Journal of Immunology

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“…This contrasts with the CD14 dependence of monophosphoryl lipid A (Supporting Information Fig. 2), which is so far the only TLR4 agonist approved as vaccine adjuvant [14,15]. Future studies will determine whether the CD14-independence of CRX-527 provides this synthetic molecule with a competitive advantage over other TLR4 agonists developed as vaccine adjuvants or stand-alone immunotherapeutics.…”

Section: Discussionmentioning

confidence: 95%

“…This contrasts with the CD14 dependence of monophosphoryl lipid A (Supporting Information Fig. 2), which is so far the only TLR4 agonist approved as vaccine adjuvant [14,15]. Future studies will determine whether the CD14-independence of CRX-527 provides Reporter luciferase gene assay HEK-TLR4 cells were cultured at 371C in a humidified 5% CO 2 atmosphere in DMEM (Lonza) supplemented by 10% FBS (Gibco), 2 mM glutamine and antibiotics (Lonza and Gibco).…”

Section: Discussionmentioning

confidence: 99%

CD14‐independent responses induced by a synthetic lipid A mimetic

et al. 2010

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CRX-527 belongs to a new family of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates, which are considered as potential vaccine adjuvants or standalone immunotherapeutics to harness innate immune defenses. Since natural lipid A from bacterial LPS depends on membrane-bound (mCD14) or soluble CD14 for its TLR4 ligand activity, we investigated the involvement of both forms of CD14 in the responses elicited by CRX-527. First, we found that CRX-527 induces NF-jB and interferon regulatory factor-3 (IRF-3) activation in human embryonic kidney cells transfected with TLR4 and MD-2 genes alone, whereas the responses to LPS require either co-transfection of the gene encoding mCD14 or addition of soluble CD14. We then observed that monocyte-derived DC, which are devoid of mCD14 respond to CRX-527 but not to LPS in serum-free medium. Furthermore, we found that, in contrast to LPS, CRX-527 induces the production of cytokines in whole blood of a patient with paroxysmal nocturnal hemoglobinuria, a disease in which mCD14-dependent responses are defective. Finally, we demonstrated that splenocytes from CD14-deficient mice produce cytokines in response to CRX-527 but not to LPS. We conclude that the lipid A mimetic CRX-527 does not require the CD14 co-receptor to elicit TLR4-mediated responses.Key words: CD14 . Lipid A . TLR4 Supporting Information available online IntroductionAminoalkyl glucosaminide phosphates lipid A mimetics are currently developed as synthetic Toll-like receptor 4 (TLR4) agonists with possible applications as vaccine adjuvants or standalone immunostimulants [1][2][3][4]. The hexa-acylate compound CRX-527, composed of three myristic and three decanoic acyl chains, has been described as one of the most powerful members of this aminoalkyl glucosaminide 4-phosphate family [5]. CD14, a GPI-anchored protein expressed at the surface of phagocytes, has been shown to be involved in the induction of TLR4-mediated responses by bacterial LPS [6,7]. Indeed, LPS was shown to bind the LPS binding protein facilitating its transfer to membranebound CD14 (mCD14), which allows LPS to engage TLR4 associated with MD-2 [6]. There is evidence that CD14 is especially important for TLR4 response mediated by the TRIF adaptor molecule, which culminates in activation of the transcription factor interferon regulatory factor-3 (IRF3) required for the production of type I interferon [8]. Cells which express TLR4 but not mCD14, such as endothelial cells and monocytederived DC (MoDC), can use the soluble form of CD14 (sCD14) to mount TLR4-mediated responses to LPS [9]. sCD14 was recently shown to discriminate slight structural differences between distinct TLR4 ligands [10]. The present study was therefore SHORT COMMUNICATION Results and discussionExpression of TLR4 and MD-2 is sufficient for the induction of NF-jB and IRF3 activities by CRX-527In preliminary experiments using transfected human embryonic kidney (HEK) cells expressing different TLR receptors, we confirmed that CRX-527 is a TLR4 agonist devoid of activity o...

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“…Data represent mean Ϯ SD of n ϭ 5 mice per dose. adjuvants (14,31). In the context of pathogen lipid recognition, TLR2 has often been implicated (32).…”

Section: Induction Of Cd8 ϩ T Cell Responses and Protective Immunity mentioning

confidence: 99%

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

Krishnan

Gurnani

Dicaire

et al. 2007

The Journal of Immunology

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Vaccines capable of eliciting long-term T cell immunity are required for combating many diseases. Live vectors can be unsafe whereas subunit vaccines often lack potency. We previously reported induction of CD8+ T cells to Ag entrapped in archaeal glycerolipid vesicles (archaeosomes). In this study, we evaluated the priming, phenotype, and functionality of the CD8+ T cells induced after immunization of mice with OVA-Methanobrevibacter smithii archaeosomes (MS-OVA). A single injection of MS-OVA evoked a profound primary response but the numbers of H-2KbOVA257–264-specific CD8+ T cells declined by 14–21 days, and <1% of primarily central phenotype (CD44highCD62Lhigh) cells persisted. A booster injection of MS-OVA at 3–11 wk promoted massive clonal expansion and a peak effector response of ∼20% splenic/blood OVA257–264-specific CD8+ T cells. Furthermore, contraction was protracted and the memory pool (IL-7Rαhigh) of ∼5% included effector (CD44highCD62Llow) and central (CD44highCD62Lhigh) phenotype cells. Recall response was observed even at >300 days. CFSE-labeled naive OT-1 (OVA257–264 TCR transgenic) cells transferred into MS-OVA-immunized recipients cycled profoundly (>90%) within the first week of immunization indicating potent Ag presentation. Moreover, ∼25% cycling of Ag-specific cells was seen for >50 days, suggesting an Ag depot. In vivo, CD8+ T cells evoked by MS-OVA killed >80% of specific targets, even at day 180. MS-OVA induced responses similar in magnitude to Listeria monocytogenes-OVA, a potent live vector. Furthermore, protective CD8+ T cells were induced in TLR2-deficient mice, suggesting nonengagement of TLR2 by archaeal lipids. Thus, an archaeosome adjuvant vaccine represents an alternative to live vectors for inducing CD8+ T cell memory.

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Enhancement of antigen-specific immunity via the TLR4 ligands MPL™ adjuvant and Ribi.529

Cited by 227 publications

References 14 publications

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

CD14‐independent responses induced by a synthetic lipid A mimetic

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

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