The Respiratory Local Lymph Node Assay as a Tool to Study Respiratory Sensitizers

Arts, J.H.E.; Jong, Wim H. de; Triel, Jos J. van; Schijf, Marcel A.; Klerk, Arja de; Loveren, Henk Van; Kuper, C. Frieke

doi:10.1093/toxsci/kfn199

Cited by 59 publications

(28 citation statements)

References 29 publications

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“…Microscopic examination revealed treatment-related effects in NALT of rats, but not in the upper respiratory tract-draining lymph nodes of rats or in NALT and lymph nodes of mice. The absence of an effect in the upper respiratory tract-draining lymph nodes is in agreement with the results of a respiratory LLNA, in which FA was the only allergen that tested negative albeit that a relatively low concentration (3 ppm) of FA was used (Arts et al, 2008).…”

Section: Discussionsupporting

confidence: 86%

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor

Kuper

Oostrum

Ma‐Hock

et al. 2011

Experimental and Toxicologic Pathology

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perplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15 ppm formaldehyde vapor. Experimental and Toxicologic Pathology, Elsevier, 2010, 63 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractTo investigate if local lymphoid tissues are a target of FA, nasopharynx-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice.Paraffin-embedded tissues were sectioned and stained with H&E or stained immunohistochemically for cell proliferation (BrdU incorporation).Light microscopy revealed simple hyperplasia of NALT lymphoepithelium of rats exposed to 15 ppm and an increased proliferation rate of the epithelial cells. Principal component (discriminant) analysis of rat NALT and lymph nodes data did not reveal other effects or effects at lower exposure levels. Mice tissues were not affected.It was concluded that hyperplasia of the lymphoepithelium of NALT of rats exposed to 15 ppm was the only distinct effect of FA vapor on local lymphoid tissues (NALT and lymph nodes) of Fischer-344 rats and B3C3F1 mice.

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Section: Discussionsupporting

confidence: 86%

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor

Kuper

Oostrum

Ma‐Hock

et al. 2011

Experimental and Toxicologic Pathology

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“…Research indicates that respiratory sensitizers may be identified through contact sensitization assays such as the LLNA, as all low-molecular-weight respiratory sensitizers tested so far were also positive in this assay (Arts et al, 2008;Boverhof et al, 2008). The unique defining characteristic of chemical respiratory allergens, which in most instances distinguishes them from contact allergens, is the ability to provoke the preferential development of T H 2-type immune responses (Kimber and Dearman, 2005).…”

Section: In Vitro Assessment Of Respiratory Sensitizersmentioning

confidence: 99%

Present and future ofin vitroimmunotoxicology in drug development

Galbiati

Mitjans

Corsini

2010

Journal of Immunotoxicology

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“…Moreover, it is possible that in an occupational context, encounter with chemicals at skin surfaces, particularly resulting from accidents and spillages, may facilitate exposure locally to high concentrations of chemical that will favour elicitation of an immune response. In this context it is likely that inhalation exposure will be less likely to result in high local concentrations of the chemical within the respiratory tract (Arts et al, 2008). Moreover, in the case of inhalation exposure it may be that the duration of exposure and concentration are important factors determining the likelihood that immunological priming will occur (Karol et al, 1986).…”

Section: Routes Of Exposurementioning

confidence: 99%

“…The activity of respiratory sensitising chemicals in the assay indicates the LLNA could, in principle, be used for the assessment of the potency of, and induction thresholds for, chemical respiratory allergens. There is a modification of the assay in which exposure is via inhalation, rather than by skin contact, and that approach could be used in a similar way (Arts et al, 2008;De Jong et al, 2009).…”

Section: The Local Lymph Node Assaymentioning

confidence: 99%

“…The general approach taken has been to expose mice via inhalation, daily for 3 consecutive days, and subsequently to measure lymphocyte proliferation in draining (mandibular) lymph nodes. A number of chemical respiratory allergens has been examined using this method, and in many instances a doseresponse relationship could be measured (Arts et al, 2008;De Jong et al, 2009). Some versions of this approach combine measurement of lymph node activation with cytokine production (De Jong et al, 2009;Johnson et al, 2011).…”

Section: Lymphocyte Proliferative Responsesmentioning

confidence: 99%

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Thresholds in chemical respiratory sensitisation

et al. 2015

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There is a continuing interest in determining whether it is possible to identify thresholds for chemical allergy. Here allergic sensitisation of the respiratory tract by chemicals is considered in this context. This is an important occupational health problem, being associated with rhinitis and asthma, and in addition provides toxicologists and risk assessors with a number of challenges. In common with all forms of allergic disease chemical respiratory allergy develops in two phases. In the first (induction) phase exposure to a chemical allergen (by an appropriate route of exposure) causes immunological priming and sensitisation of the respiratory tract. The second (elicitation) phase is triggered if a sensitised subject is exposed subsequently to the same chemical allergen via inhalation. A secondary immune response will be provoked in the respiratory tract resulting in inflammation and the signs and symptoms of a respiratory hypersensitivity reaction. In this article attention has focused on the identification of threshold values during the acquisition of sensitisation. Current mechanistic understanding of allergy is such that it can be assumed that the development of sensitisation (and also the elicitation of an allergic reaction) is a threshold phenomenon; there will be levels of exposure below which sensitisation will not be acquired. That is, all immune responses, including allergic sensitisation, have threshold requirement for the availability of antigen/allergen, below which a response will fail to develop. The issue addressed here is whether there are methods available or clinical/epidemiological data that permit the identification of such thresholds. This document reviews briefly relevant human studies of occupational asthma, and experimental models that have been developed (or are being developed) for the identification and characterisation of chemical respiratory allergens. The main conclusion drawn is that although there is evidence that the acquisition of sensitisation to chemical respiratory allergens is a dose-related phenomenon, and that thresholds exist, it is frequently difficult to define accurate numerical values for threshold exposure levels. Nevertheless, based on occupational exposure data it may sometimes be possible to derive levels of exposure in the workplace, which are safe. An additional observation is the lack currently of suitable experimental methods for both routine hazard characterisation and the measurement of thresholds, and that such methods are still some way off. Given the current trajectory of toxicology, and the move towards the use of non-animal in vitro and/or in silico) methods, there is a need to consider the development of alternative approaches for the identification and characterisation of respiratory sensitisation hazards, and for risk assessment.

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The Respiratory Local Lymph Node Assay as a Tool to Study Respiratory Sensitizers

Cited by 59 publications

References 29 publications

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor

Present and future ofin vitroimmunotoxicology in drug development

Thresholds in chemical respiratory sensitisation

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