<scp>MPLA</scp> shows attenuated pro‐inflammatory properties and diminished capacity to activate mast cells in comparison with <scp>LPS</scp>

Schülke, Stefan; Flaczyk, Adam; Vogel, Lothar; Gaudenzio, Nicolas; Angers, Isabelle; Löschner, Bettina; Wolfheimer, Sonja; Spreitzer, Ingo; Qureshi, Salman T.; Tsai, Mindy; Galli, Stephen J.; Vieths, Stefan; Scheurer, Stephan

doi:10.1111/all.12675

Cited by 42 publications

(33 citation statements)

References 31 publications

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“…Most types of native LPS are potent inducers of NLRP3 inflammasome activation and induce a potent pro-inflammatory response. In agreement with our results, Schülke and colleagues showed that, as compared to its parent molecule LPS, MPLA induced a qualitatively similar but significantly less potent pro-inflammatory immune response in in vitro, ex vivo , and in vivo human and mouse test systems22. They further successfully generated a novel fusion protein consisting of MPLA and a model allergen Ovalbumin (MPLA : Ova), and demonstrated that MPLA : Ova can boost Th1, Th2, and Th17 TC-derived cytokine secretion and hence induce both stronger innate and adaptive immune responses compared to the mixture of both components23.…”

Section: Discussionsupporting

confidence: 93%

Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Luan

Patil

Guo

et al. 2017

Sci Rep

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Monophosphoryl lipid A (MPLA), a less toxic derivative of lipopolysaccharide (LPS), is employed as a vaccine adjuvant and is under investigation as a non-specific immunomodulator. However, the differential response of human leukocytes to MPLA and LPS has not been well characterized. The goal of this study was to compare the differential transcriptomic response of human blood to LPS and MPLA. Venous blood from human volunteers was stimulated with LPS, MPLA or vehicle. Gene expression was determined using microarray analysis. Among 21,103 probes profiled, 136 and 130 genes were differentially regulated by LPS or MPLA, respectively. Seventy four genes were up-regulated and 9 were down-regulated by both ligands. The remaining genes were differentially induced by either agent. Ingenuity Pathway Analysis predicted that LPS and MPLA share similar upstream regulators and have comparable effects on canonical pathways and cellular functions. However, some pro-inflammatory cytokine and inflammasome-associated transcripts were more strongly induced by LPS. In contrast, only the macrophage-regulating chemokine CCL7 was preferentially up-regulated by MPLA. In conclusion, LPS and MPLA induce similar transcriptional profiles. However, LPS more potently induces pro-inflammatory cytokine and inflammasome-linked transcripts. Thus, MPLA is a less potent activator of the pro-inflammatory response but retains effective immunomodulatory activity.

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Section: Discussionsupporting

confidence: 93%

Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Luan

Patil

Guo

et al. 2017

Sci Rep

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“…Monophosphoryl lipid A (MPLA), a detoxified derivative of lipid A from lipopolysaccharide (LPS), has been approved by FDA and widely used for vaccine studies. Although safer than LPS, its adjuvant activity is also significantly reduced [18]. Therefore, further improvement of its adjuvant effect is still required.…”

Section: Introductionmentioning

confidence: 99%

Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine

et al. 2017

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Although re-activating cytotoxic T-cell (CTLs) response inside tumor tissues by checkpoint blockade has demonstrated great success in tumor immunotherapy, active induction of efficient endogenous CTL response by therapeutic vaccines has been largely hampered by inefficient cytosolic delivery of antigens and coordinated activation of dendritic cells (DCs) in lymph nodes. Here we show that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles transform soluble peptides into α-helix to enable their efficient cytosolic delivery. The same PEG-PE micelles also serve as chaperon of TLR4 signaling to coordinate its adjuvant effect on the same DCs. Furthermore, these nanovaccines effectively target lymph node DCs. Thus, PEG-PE micelle vaccines program at multiple key aspects for inducing strong CTL responses and build up a foundation for combinational tumor therapy.

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“…MPLA is a nontoxic TLR4 ligand that is considered as a promising immune stimulator due to its ability to trigger the induction of pro‐inflammatory cytokines . It has been used as an adjuvant in the development of cancer vaccines and malaria vaccines, and in allergen‐specific immunotherapy . In the current study, MPLA was incorporated into EXOs together with TRP2 using the saponin incubation method.…”

mentioning

confidence: 99%

Efficient Delivery of Tyrosinase Related Protein‐2 (TRP2) Peptides to Lymph Nodes using Serum‐Derived Exosomes

Park

Choi

et al. 2018

Macromolecular Bioscience

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Exosomes (EXO) are considered to be versatile carriers for biomolecules; however, the delivery of therapeutic peptides using EXOs poses several challenges. In this study, the efficiency of serum‐derived EXOs in delivering tyrosinase‐related protein‐2 (TRP2) peptides to lymph nodes is determined. TRP2 peptides are successfully incorporated into EXOs, which show a uniform and narrow size distribution of around 45 nm. The TRP2‐incorporated exosomes (EXO‐TRP2) are efficiently internalized into macrophages and dendritic cells, and are seen to display a punctate distribution. EXOs loaded with TRP2 together with MPLA, (EXO‐MPLA‐TRP2) result in a strong release of proinflammatory cytokines (TNF‐α and IL‐6) from both RAW264.7 and DC2.4 cells. Finally, subcutaneous injection of fluorescently labeled EXO‐TRP2 followed by ex vivo imaging using in vivo imaging system (IVIS) show a strong fluorescent signal in the lymph nodes after only 1 h, which is maintained until at least 4 h after injection. Taken together, the findings suggest that serum‐derived EXOs can serve as promising carriers to deliver therapeutic peptides to lymph nodes for immunotherapy.

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MPLA shows attenuated pro‐inflammatory properties and diminished capacity to activate mast cells in comparison with LPS

Abstract: Compared to LPS, MPLA induced a qualitatively similar, but less potent pro-inflammatory immune response, but was unable to activate human or mouse MCs.

Cited by 42 publications

References 31 publications

Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine

Efficient Delivery of Tyrosinase Related Protein‐2 (TRP2) Peptides to Lymph Nodes using Serum‐Derived Exosomes

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