Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices

Switalla, Simone; Lauenstein, L.; Prenzler, Frauke; Knothe, S.; Förster, Christine; Fieguth, Hans‐Gerd; Pfennig, Olaf; Schaumann, Frank; Martin, Christian; Guzmán, Carlos A.; Ebensen, Thomas; Müller, Meike; Hohlfeld, Jens M.; Krug, Norbert; Braun, Armin; Sewald, Katherina

doi:10.1016/j.taap.2010.04.010

Cited by 61 publications

(65 citation statements)

References 54 publications

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“…The resulting inflammatory response is highly comparable to the in vivo situation as it is observed for patients after inhalation of lPS (Switalla et al, 2010). this model was challenged with the Sens-it-iv set of chemicals (Tab.…”

Section: Validation and Regulatory Proceduressupporting

confidence: 55%

Advanced tests for skin and respiratory sensitization assessment

Rovida

Martin

Vivier

et al. 2013

ALTEX

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Denmark, aided by the vice-coordinator Hans-Ulrich Weltzien from the Max-Planck Institute for Immunobiology and epigenetics, Freiburg Germany. the ultimate goal of the Sens-it-iv project was the development of a set of in vitro methods for the assessment of the skin and respiratory sensitization potential of chemicals and proteins. the level of development was intended to be at the point to enter the pre-validation phase. After 66 months of work, it could be concluded that the goal was largely accomplished. Several advanced methods were evaluated extensively, and for some of them a detailed standard operating procedure (SOP) was established for pre-validation purposes. Other, less advanced methods contributed to our understanding of the mechanisms driving sensitization as well.Several opportunities were employed to assure dissemination of results. During the course of the project, 44 newsletters were released, presenting the main achievements of the project. Fly-1 Introduction

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Section: Validation and Regulatory Proceduressupporting

confidence: 55%

Advanced tests for skin and respiratory sensitization assessment

Rovida

Martin

Vivier

et al. 2013

ALTEX

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“…Unlike Switalla et al, we did not detect IL-12p40 or IFN-g production in culture supernatants, potentially due to a different duration of LPS stimulation (18 vs. 24 hours). 18 We then explored if PCLS in culture could specifically respond to common antigen stimulation. It has already been shown that human lung slices exposed to live influenza virus induce a strong pro-inflammatory cytokine and chemokine response.…”

Section: Discussionmentioning

confidence: 99%

“…These processes are characterized by activation or suppression of certain mediators, which can be used as tools for evaluation of immune modulating effects of target products. 13,[16][17][18] In the current study, we characterize a human PCLS cultivation system that was established to assess the ability of human PCLS to develop inflammatory and immune responses to antigen stimulation. Results demonstrated that PCLS remained viable, structurally intact and able to elicit functional responses up to 14 d in culture.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

Temann

Golovina

Neuhaus

et al. 2016

Human Vaccines & Immunotherapeutics

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The development of systems that are more accurate and time-efficient in predicting safety and efficacy of target products in humans are critically important in reducing the cost and duration of pharmaceutical development. To circumvent some of the limitations imposed by the use of animal models, ex vivo systems, such as precision-cut lung slices (PCLS), have been proposed as an alternative for evaluating safety, immunogenicity and efficacy of vaccines and pharmaceuticals. In this study, we have established a human PCLS system and methodology for PCLS cultivation that can provide long-term viability and functionality in culture. Using these techniques, we found that cultured PCLS remained viable for at least 14 d in culture and maintained normal metabolic activity, tissue homeostasis and structural integrity. To investigate whether cultured PCLS remained functional, lipopolysaccharide (LPS) was used as a target stimulating compound. We observed that after an 18-hour incubation with LPS, cultured PCLS produced a set of pro-inflammatory cytokines, including TNF-a, IL-1b, IL-6 and IL-10 as well as the enzyme COX-2. Furthermore, cultured PCLS were shown to be capable of generating re-call immune responses, characterized by cytokine production, against antigens commonly found in routine vaccinations against influenza virus and tetanus toxoid. Taken together, these results suggest that human PCLS have the potential to be used as an alternative, high-throughput, ex vivo system for evaluating the safety, and potentially immunogenicity, of vaccines and pharmaceuticals.

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“…Bisacyloxypropylcysteine polyethylene glycol (BPPcysMPEG)is a derivate of MALP-2 that is also capable of stimulating TLR2/6 and also has the ability to abrogate Th2 response and airway eosinophilia in murine asthma models [56]. BPPcysMPEG exerts its immunomodulatory effects by inducing production of IL-1β, chemokine (C-C motif) ligand 4 (CCL4; macrophage inflammatory protein-1β) and IL-10 in viable precision-cut slices of lung tissues in vitro [57]. Both systemic and local delivery of BPPcysMPEG with allergens leads to the maturation of DCs and induction of appropriate adaptive immune response against the allergen in sensitized mice [58].…”

Section: Tlr1 2 6 and 10mentioning

confidence: 99%

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

Aryan

Holgate

Radzioch

et al. 2014

Int Arch Allergy Immunol

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Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient ‘gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available ‘curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge.

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Natural innate cytokine response to immunomodulators and adjuvants in human precision-cut lung slices

Cited by 61 publications

References 54 publications

Advanced tests for skin and respiratory sensitization assessment

Advanced tests for skin and respiratory sensitization assessment

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

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