Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells

Ouwehand, Krista; Spiekstra, Sander W.; Reinders, Judith; Scheper, Rik J.; Gruijl, Tanja D. de; Gibbs, Susan

doi:10.1016/j.tiv.2009.10.014

Cited by 45 publications

(31 citation statements)

References 23 publications

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“…While these cell lines are generally used in their na ï ve state, it is also possible to induce a more DC-like phenotype. This particularly holds true for the MUTZ-3 cells, which cannot only be diff erentiated toward a dendritic cell, but also a Langerhans cell phenotype (Ouwehand et al 2010). Results from the transcriptomics analysis showed that cells with DC characteristics (CD34 ϩ DC, monocyte DC, U937, THP-1, and MUTZ-3) provided signals related to DC activation and maturation (Figure 1, step 4).…”

Section: Dc-like Cell Sourcesmentioning

confidence: 92%

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

Veen

Soeteman‐Hernández

Ezendam

et al. 2014

Critical Reviews in Toxicology

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Allergic contact dermatitis (ACD) is a hypersensitivity immune response induced by small protein-reactive chemicals. Currently, the murine local lymph node assay (LLNA) provides hazard identification and quantitative estimation of sensitizing potency. Given the complexity of ACD, a single alternative method cannot replace the LLNA, but it is necessary to combine methods through an integrated testing strategy (ITS). In the development of an ITS, information regarding mechanisms and molecular processes involved in skin sensitization is crucial. The recently published adverse outcome pathway (AOP) for skin sensitization captures mechanistic knowledge into key events that lead to ACD. To understand the molecular processes in ACD, a systematic review of murine in vivo studies was performed and an ACD molecular map was constructed. In addition, comparing the molecular map to the limited human in vivo toxicogenomic data available suggests that certain processes are similarly triggered in mice and humans, but additional human data will be needed to confirm these findings and identify differences. To gain insight in the molecular mechanisms represented by various human in vitro systems, the map was compared to in vitro toxicogenomic data. This analysis allows for comparison of emerging in vitro methods on a molecular basis, in addition to mathematical predictive value. Finally, a survey of the current in silico, in chemico, and in vitro methods was used to indicate which AOP key event is modeled by each method. By anchoring emerging classification methods to the AOP and the ACD molecular map, complementing methods can be identified, which provides a cornerstone for the development of a testing strategy that accurately reflects the key events in skin sensitization.

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Section: Dc-like Cell Sourcesmentioning

confidence: 92%

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

Veen

Soeteman‐Hernández

Ezendam

et al. 2014

Critical Reviews in Toxicology

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“…Cells were cultured at 37°C, 5% CO 2, 95% humidity. MUTZ-LC were labeled with carboxyfluorescein succinimidyl ester (CFSE) as described previously (Ouwehand et al, 2010b).…”

Section: Cell Culturementioning

confidence: 99%

“…This cell line can be differentiated in a Transforming Growth Factor (TGF)-β-dependent fashion into LC (MUTZ-LC), expressing Langerin and bearing LC-associated Birbeck granules (Masterson et al, 2002;Santegoets et al, 2006). In mono-culture, upon stimulation with maturation inducing factors (including allergens), MUTZ-LC expressed characteristic maturation markers, such as CD83, CXCR4 and CCR7, and acquired the ability to migrate towards CXCL12, thus closely resembling their in vivo counterparts (Larsson et al, 2006;Ouwehand et al, 2008, Ouwehand et al, 2010b. When MUTZ-LC were incorporated into full-thickness SE they showed the ability to mature and migrate from the epidermis into the dermis after topical exposure of the stratum corneum to the allergens nickel sulfate and resorcinol (Ouwehand et al, 2011b).…”

Section: Introductionmentioning

confidence: 99%

MUTZ-3 derived Langerhans cells in human skin equivalents show differential migration and phenotypic plasticity after allergen or irritant exposure

Kosten

Spiekstra

Gruijl

et al. 2015

Toxicology and Applied Pharmacology

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After allergen or irritant exposure, Langerhans cells (LC) undergo phenotypic changes and exit the epidermis. In this study we describe the unique ability of MUTZ-3 derived Langerhans cells (MUTZ-LC) to display similar phenotypic plasticity as their primary counterparts when incorporated into a physiologically relevant full-thickness skin equivalent model (SE-LC). We describe differences and similarities in the mechanisms regulating LC migration and plasticity upon allergen or irritant exposure. The skin equivalent consisted of a reconstructed epidermis containing primary differentiated keratinocytes and CD1a(+) MUTZ-LC on a primary fibroblast-populated dermis. Skin equivalents were exposed to a panel of allergens and irritants. Topical exposure to sub-toxic concentrations of allergens (nickel sulfate, resorcinol, cinnamaldehyde) and irritants (Triton X-100, SDS, Tween 80) resulted in LC migration out of the epidermis and into the dermis. Neutralizing antibody to CXCL12 blocked allergen-induced migration, whereas anti-CCL5 blocked irritant-induced migration. In contrast to allergen exposure, irritant exposure resulted in cells within the dermis becoming CD1a(-)/CD14(+)/CD68(+) which is characteristic of a phenotypic switch of MUTZ-LC to a macrophage-like cell in the dermis. This phenotypic switch was blocked with anti-IL-10. Mechanisms previously identified as being involved in LC activation and migration in native human skin could thus be reproduced in the in vitro constructed skin equivalent model containing functional LC. This model therefore provides a unique and relevant research tool to study human LC biology in situ under controlled in vitro conditions, and will provide a powerful tool for hazard identification, testing novel therapeutics and identifying new drug targets.

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“…There are a variety of proposed test methods based on the use of cultured DC, or DC-like cell lines, the theory being that exposure of such cells to skin sensitizing chemicals, but not to non-sensitizers, will provoke functional or phenotypic changes that will serve as biomarkers of sensitizing activity and as readouts for cell-based assay systems Arkusz et al, 2010;Ashikaga et al, 2010;Ouwehand et al, 2010;Python et al, 2007;Johansson et al, 2011). There is no doubt that some of these assays perform rather well and show real promise.…”

Section: Special Research Areasmentioning

confidence: 99%

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

Basketter

Clewell

Kimber

et al. 2012

ALTEX

203

165

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Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells

Cited by 45 publications

References 23 publications

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

MUTZ-3 derived Langerhans cells in human skin equivalents show differential migration and phenotypic plasticity after allergen or irritant exposure

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

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