Mycobacterial and mouse HSP70 have immuno-modulatory effects on dendritic cells

Spiering, Rachel; Zee, Ruurd van der; Wagenaar, J.A.; Eden, Willem van; Broere, Femke

doi:10.1007/s12192-012-0397-4

Cited by 27 publications

(20 citation statements)

References 39 publications

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“…25,26 In this study we compared T cell mediated peptide specific immune responses to SAV assembled with both shorter (40-45 amino acids) peptides and (60-65 amino acids) concatenated peptides. The vaccine with shorter peptides (SAV1) was comprised of an equimolar mixture of 4 different protein-peptide constructs, with each construct containing one of the 4 class II epitopes.…”

Section: Peptide Design Optimization Using An Ovalbumin Immunization mentioning

confidence: 99%

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

Leblanc

Moise

Luza

et al. 2014

Human Vaccines & Immunotherapeutics

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Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d. A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-g CD4C T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.

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Section: Peptide Design Optimization Using An Ovalbumin Immunization mentioning

confidence: 99%

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

Leblanc

Moise

Luza

et al. 2014

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

show abstract

“…Upregulation of DnaK and the S -adenosylmethionine synthase might also negatively impact on the virulence of the bacterium. The former is the major bacterial counterpart of the heat shock protein 70, found to act as an important immunomodulator of monocytes, dendritic cells (49–51), and macrophage responses. It has been recognized as being capable of polarizing macrophages to the M2 phenotype by inducing higher arginase I activity, IL-10 production, and FIZZ1 and Ym1 expression (33).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin Attenuates Pseudomonas-Induced Lung Inflammation by Targeting Bacterial Proteins Secreted in the Cultured Medium

et al. 2016

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BackgroundPseudomonas aeruginosa airway infections are a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Azithromycin improves the related clinical outcomes, but its mechanisms of action remain poorly understood. We tested the hypothesis that azithromycin downregulates P. aeruginosa-induced pro-inflammatory responses by modifying release of bacterial proteins.MethodsWe monitored inflammatory markers in lungs of CF mutant mice and their littermate controls in response to conditioned media (CM) collected from the reference P. aeruginosa PAO1 strain cultured in the presence or in the absence of azithromycin. A mass spectrometry-based proteomic approach was applied to examine whether the macrolide elicits a differential release of bacterial proteins.ResultsCM collected from azithromycin-untreated PAO1 cultures induced powerful pro-inflammatory neutrophil-dominated responses. Azithromycin attenuated the responses, mainly of macrophage chemoattractant protein-1, tumor necrosis factor-α, and interferon-γ, in CF but not in wild-type mice. Proteomic analysis showed that azithromycin upregulated an array of bacterial proteins including those associated with regulation of immune functions and with repair and resolution of inflammatory responses like the chaperone DnaK and the S-adenosylmethionine synthase, while it downregulated the extracellular heme acquisition protein HasA and the catalytic enzyme lysylendopeptidase.ConclusionSupernatants collected from cultures of the bacterial strain PAO1 represent a novel experimental model to trigger in vivo lung inflammatory responses that should be closer to those obtained with live bacteria, but without bacterial infection. Combined with a bactericidal effect, complex regulation of bacterial innate immune and metabolic factors released in the cultured medium by the action of the macrolide can contribute to its anti-inflammatory effects.

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“…Next to the Treg cell inducing potential of B29, bone‐marrow‐derived DCs pulsed with Mycobacterium tuberculosis or mouse HSP 70 induced IL‐10 production in antigen‐specific T cells and suppressed arthritis, showing that HSP 70 loading of DCs by itself is tolerizing …”

Section: Hsps As Surrogate Autoantigens For Autoimmunitymentioning

confidence: 99%

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

et al. 2017

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SummaryTolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens.

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Mycobacterial and mouse HSP70 have immuno-modulatory effects on dendritic cells

Cited by 27 publications

References 39 publications

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

VaxCelerate II: Rapid development of a self-assembling vaccine for Lassa fever

Azithromycin Attenuates Pseudomonas-Induced Lung Inflammation by Targeting Bacterial Proteins Secreted in the Cultured Medium

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

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