Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure

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

doi:10.1016/j.tox.2009.04.057

Cited by 51 publications

(40 citation statements)

References 33 publications

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“…However, different allergens cause widely divergent immune responses, making it difficult to predict mechanisms and therapeutic strategies for ACD elicited by common environmental allergens such as urushiol (25,26). We therefore optimized and characterized a mouse model of poison ivy ACD and applied transcriptomic, biochemical, neurophysiological, and behavioral methods to identify the inflammatory and pruritic mechanisms engaged in murine poison ivy ACD.…”

Section: Discussionmentioning

confidence: 99%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

222

195

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Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO 2 . Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca 2+ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.A llergic contact dermatitis (ACD) is a common allergic skin condition caused by environmental or occupational allergens (1). In the United States, the most common cause of ACD is contact with poison ivy, which affects >10 million Americans per year (2, 3). Poison ivy ACD is also a serious occupational hazard, particularly among firefighters, forestry workers, and farmers, accounting for 10% of total U.S. Forest Services losttime injuries, and it often torments outdoor enthusiasts as well (3, 4). The major allergen in poison ivy is urushiol, contained in the oleoresinous sap of the plant and of related plants (e.g., poison oak and poison sumac) (5). An estimated 50-75% of Americans are sensitized to urushiol (6). Elevated atmospheric carbon dioxide and warming temperatures have increased the biomass of poison ivy and related plants, widened their geographic distribution, and increased plant urushiol content (7). These factors will likely increase allergenicity and result in even larger case numbers of poison ivy ACD in the future (8).The clinical manifestations of poison ivy-induced ACD are intense and persistent itch (pruritus), burning sensation, skin rashes, and swelling, followed by the appearance of vesicles in severe cases (2, 3, 9). Skin inflammation and pruritus ...

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Section: Discussionmentioning

confidence: 99%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

222

195

View full text Add to dashboard Cite

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“…Although experience in some experimental systems has been varied, it appears that, probably irrespective of the route of exposure, chemical respiratory allergens induce selective Th2-type immune responses, characterised by the preferential expression of type 2 cytokines (including interleukins 4, 5 and 13). It is argued also that skin and respiratory chemical allergens induce distinct cytokine secretion patterns (Th1-and Th2-type, respectively), and that this may provide a basis for distinguishing between these allergens in the context of hazard characterisation (Kimber and Dearman, 1997a;Dearman and Kimber, 2001;Dearman et al, 2002;Plitnick et al, 2002;Selgrade et al, 2006;De Jong et al, 2009;Kimber et al, 2011;Adenuga et al, 2012). Although evidence for the differential immunological selectivity of contact and respiratory chemical allergens has been based largely on studies in experimental animals, there is emerging evidence that the same, or at least similar, patterns are seen in humans (Toebak et al, 2006;Kimber et al, 2013;Newell et al, 2013;Ouyang et al, 2013).…”

Section: Mechanisms Through Which Sensitisation Of the Respiratory Trmentioning

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%

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 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). Discrimination between contact and respiratory sensitizers can be eventually achieved in vivo by the assessment of cytokine profiles (Dearman et al, 2002;de Jong et al, 2009).…”

Section: In Vitro Assessment Of Respiratory Sensitizersmentioning

confidence: 99%