TLR-based immune adjuvants

Steinhagen, Folkert; Kinjo, Takeshi; Bode, Christian; Klinman, Dennis M.

doi:10.1016/j.vaccine.2010.08.002

Cited by 437 publications

(391 citation statements)

References 248 publications

(208 reference statements)

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“…Although TLR agonists have often been used in experimental and clinical studies as an immune adjuvant [27], many are associated with significant side effects or toxicity [37,38]. FimH represents a recently discovered TLR4 ligand with a great potential to be a safe and effective immune modulator, particularly amenable for mucosal application based on its selective effect on APCs [39].…”

Section: Discussionmentioning

confidence: 99%

“…Certain TLR agonists are capable of innate immune activation and have been explored as immune adjuvant in vaccine formulations [27]. In this regard, we have recently identified the TLR4 agonist FimH, the adhesion portion of Escherichia coli type I fimbriae, to be a potent immune activator with a major effect on DC in the lungs [28], thus making it an attractive candidate immune modulator in our model.…”

Section: Restoration Of Innate Immune Activation By Intranasal Fimh Dmentioning

confidence: 99%

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Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.Keywords: DCs r Delayed Th1 immunity r FimH r Mycobacterium r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPulmonary mycobacterial infection is mainly caused by Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), and by other slow growing less virulent nontuberculous Correspondence: Dr. Zhou Xing e-mail: xingz@mcmaster.ca mycobacterial (NTM) species including M. avium and M. kasasii. The continuing high global incidence of and death due to tuberculosis infections [1] and the dramatic increase in pulmonary NTM disease globally over the past three decades [2] underscores the need to further understand the complex host immune responses to mycobacterial exposure in order to develop effective prophylactic and therapeutic strategies.Protective immunity against mycobacterial infection requires the presence of a robust adaptive Th1-type response at the site of Eur. J. Immunol. 2014Immunol. . 44: 1375Immunol. -1386 infection. Upon exposure to the bacterium, mycobacteria is taken up by sentinel APCs such as DCs and delivered to the draining lymph node (dLN) [3,4]. On arrival, these APCs present mycobacterial antigen to naive T cells within the dLN, thereby priming the antigen-specific T cells to a Th1 phenotype and stimulating their expansion [5]. The Th1 cells are then recruited back to the site of infection, and the secretion of Th1 cytokines such as IFN-γ by these cells is critical to activation of infected APCs to control bacterial growth [6]. However, one of the defining characteristics of host defense toward mycobacterial patho...

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Section: Discussionmentioning

confidence: 99%

Section: Restoration Of Innate Immune Activation By Intranasal Fimh Dmentioning

confidence: 99%

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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“…Administration of siRNA via liposomes or transgenic reagent Lipofectamine® induce potent immunostimulation generating TH1 inflammatory cytokines from human monocytes and plasmacytoid dendritic cells [66,67]. In addition, immune responses through TLRs' signals cause adoptive immunity, such as the generation of antibody [68]. It is of importance to study the mechanism of signal transduction associated with TLRs for understanding of the generation of undesirable immune responses.…”

Section: Pattern Recognition-mediated Inflammatory Responsesmentioning

confidence: 99%

Endocytosis of Particle Formulations by Macrophages and Its Application to Clinical Treatment

Hirota¹,

Terada²

2012

Molecular Regulation of Endocytosis

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“…9,10 TLR agonists have also been shown to enhance therapeutic vaccination against cancer and chronic viral infections. 8,11,14 Indeed, vaccines containing the adjuvant AS04, made by the alum-absorbed TLR4 agonist monophosphoryl lipid A (MPL), have been approved for human use in 2005. 1,15 Here we explored the ability of SMIP2.1, a novel synthetic lipopeptide-based TLR2 agonist, to induce cross-presentation by both mouse and human APCs.…”

Section: Cd8mentioning

confidence: 99%

A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells

Santone

Aprea

et al. 2015

Human Vaccines & Immunotherapeutics

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Cross-presentation is the process by which professional APCs load peptides from an extracellularly derived protein onto class I MHC molecules to trigger a CD8 C T cell response. The ability to enhance this process is therefore relevant for the development of antitumor and antiviral vaccines. We investigated a new TLR2-based adjuvant, Small Molecule Immune Potentiator (SMIP) 2.1, for its ability to stimulate cross-presentation. Using OVA as model antigen, we demonstrated that a SMIP2.1-adjuvanted vaccine formulation induced a greater CD8C T cell response, in terms of proliferation, cytokine production and cytolytic activity, than a non-adjuvanted vaccine. Moreover, using an OVAexpressing tumor model, we showed that the CTLs induced by the SMIP2.1 formulated vaccine inhibits tumor growth in vivo. Using a BCR transgenic mouse model we found that B cells could cross-present the OVA antigen when stimulated with SMIP2.1. We also used a flow cytometry assay to detect activation of human CD8 C T cells isolated from human PBMCs of cytomegalovirus-seropositive donors. Stimulation with SMIP2.1 increased the capacity of human APCs, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8 C T cells. Therefore, vaccination with an exogenous antigen formulated with SMIP2.1 is a successful strategy for the induction of a cytotoxic T cell response along with antibody production.

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TLR-based immune adjuvants

Cited by 437 publications

References 248 publications

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Endocytosis of Particle Formulations by Macrophages and Its Application to Clinical Treatment

A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells

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