Contact-Sensitizing and Tolerogenic Properties of 2,4-Dinitrothiocyanobenzene

Kimber, Ian; Botham, Philip A.; Rattray, N.J.; Walsh, Stuart T.

doi:10.1159/000234144

Cited by 22 publications

(14 citation statements)

References 9 publications

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“…Finally, our results may shed some light on the controversy regarding the sensitizing potential of DNTB. Indeed, unlike several reports, including the present work, some authors did not observe tolerance to DNTB but a weaker sensitization, concomitant with dendritic cell accumulation in regional lymph nodes (17,18). We propose that the frontier between tolerance and sensitization is narrow and easily crossed.…”

Section: Discussioncontrasting

confidence: 94%

“…Our data are consistent with previously published observations and tend to confirm that DNFB and DNTB provide epitopes that can be recognized by the same T cells, yet differ in their capacity to prime the adaptive immunity (11,12,16). Although the value of DNTB as a tolerogen is still debated (17,18), this suggests that the level of inflammasome signaling induced by a given molecule may better predict its sensitizing potential than the antigenic properties itself.…”

Section: Dnfb and Dntb Provide Similar Epitopes Yet Differ In Their Cmentioning

confidence: 99%

“…Indeed, some find it to behave as a weak sensitizer (17,18), whereas others find it induces tolerance (11,13,14). There is, on the contrary, no doubt on the fact that DNFB is a strong sensitizer.…”

Section: Exposure To Topical Sensitizers In the Absence Of Inflammasomentioning

confidence: 99%

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Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance and Sensitization

Watanabe

Gehrke

Contassot

et al. 2008

The Journal of Immunology

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Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1β is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo.

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Section: Discussioncontrasting

confidence: 94%

Section: Dnfb and Dntb Provide Similar Epitopes Yet Differ In Their Cmentioning

confidence: 99%

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Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance and Sensitization

Watanabe

Gehrke

Contassot

et al. 2008

The Journal of Immunology

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“…By contrast, in experimental animals, topically applied 2,4-dinitrothiocyanobenzene (DNTB) has been reported by some authors to be capable of inducing immunological tolerance to itself and to cross-reactive dinitrophenyl compounds (3)(4)(5)(6). However, other authors could not demonstrate induction of tolerance by DNTB, but instead found it induced contact sensitivity in mice, rats, and a single human volunteer (7)(8)(9). It has been postulated that DNCB and DNTB form similar haptenated compounds in vivo; thus, the questions that arise based on the previous research are whether DNCB and DNTB provoke different cutaneous immune responses, and what forms the basis of any differences.…”

mentioning

confidence: 98%

The Cutaneous Biochemical Redox Barrier: A Component of the Innate Immune Defenses against Sensitization by Highly Reactive Environmental Xenobiotics

Pickard

Louafi

McGuire

et al. 2009

The Journal of Immunology

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Contact allergy to environmental xenobiotics is a common and important problem, but it is unclear why some chemicals are potent sensitizers and others weak/nonsensitizers. We explored this by investigating why similar chemicals, 2,4-dinitrochlorobenzene (DNCB) and 2,4-dinitrothiocyanobenzene (DNTB), differ in their ability to induce contact hypersensitivity (CHS). DNCB induced CHS in humans, whereas at similar doses DNTB did not. However, following DNCB sensitization, DNTB elicited CHS in vivo and stimulated DNCB-responsive T cells in vitro, suggesting that differences in response to these compounds lie in the sensitization phase. In contrast to DNCB, DNTB failed to induce emigration of epidermal Langerhans cells in naive individuals. Examination for protein dinitrophenylation in skin revealed that DNCB penetrated into the epidermis, whereas DNTB remained bound to a thiol-rich band within the stratum corneum. DNTB reacted rapidly with reduced glutathione in vitro and was associated with a decrease in the free thiol layer in the stratum corneum, but not in the nucleated epidermis. By contrast, DNCB required GST facilitation to react with gluthathione and, following penetration through the stratum corneum, depleted thiols in the viable epidermis. Chemical depletion of the thiol-rich band or removing it by tape stripping allowed increased penetration of DNTB into the epidermis. Our results suggest that the dissimilar sensitizing potencies of DNCB and DNTB in humans are determined by a previously undescribed outer epidermal biochemical redox barrier, a chemical component of the innate immune defense mechanisms that defend against sensitization by highly reactive environmental chemicals.

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“…Contact hypersensitivity (CHS) is a classic experimental model for the study of antigen-specific, T cell-mediated immune responses (1)(2)(3)(4). In CHS, typified by poison ivy dermatitis, initial sensitization occurs by topical application of an immunizing antigen, processing of antigen by skin dendritic cells (i.e., Langerhans cells), migration of antigen-bearing Langerhans cells to regional lymph nodes, and stimulation of naive T cells (5,6).…”

mentioning

confidence: 99%

Matrix metalloproteinase deficiencies affect contact hypersensitivity: Stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response

Wang

Qin

Mudgett

et al. 1999

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

121

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Matrix metalloproteinases (MMPs) are expressed by T cells and macrophages, but there is a paucity of evidence for their role in immune responses. We have studied mice with deficiencies of stromelysin-1 (MMP-3) or gelatinase B (MMP-9) in a dinitrof luorobenzene (DNFB)-induced model of contact hypersensitivity (CHS). Stromelysin-1-deficient mice showed a markedly impaired CHS response to topical DNFB, although they responded normally to cutaneously applied phenol, an acute irritant. Lymphocytes from lymph nodes of DNFB-sensitized stromelysin-1-deficient mice did not proliferate in response to specific soluble antigen dinitrobenzenesulfonic acid, but did proliferate identically to lymph node lymphocytes from wild-type mice when presented with the mitogen Con A. An intradermal injection of stromelysin-1 immediately before DNFB sensitization rescued the impaired CHS response to DNFB in stromelysin-1-deficient mice. Unlike stromelysin-1-deficient mice, gelatinase Bdeficient mice exhibited a CHS response comparable to wildtype controls at 1 day postchallenge, but the response persisted beyond 7 days in contrast to the complete resolution observed in wild-type mice by 7 days. However, gelatinase B-deficient mice had a normal rate of resolution of acute inf lammation elicited by cutaneous phenol. Gelatinase Bdeficient mice failed to show IL-10 production at the site of CHS, an essential feature of resolution in control mice. These results indicate that stromelysin-1 and gelatinase B serve important functions in CHS. Stromelysin-1 is required for initiation of the response, whereas gelatinase B plays a critical role in its resolution.Contact hypersensitivity (CHS) is a classic experimental model for the study of antigen-specific, T cell-mediated immune responses (1-4). In CHS, typified by poison ivy dermatitis, initial sensitization occurs by topical application of an immunizing antigen, processing of antigen by skin dendritic cells (i.e., Langerhans cells), migration of antigen-bearing Langerhans cells to regional lymph nodes, and stimulation of naive T cells (5, 6). A second exposure of the same antigen to skin then results in local influx of antigen-specific T cells, which release cytokines that attract other inflammatory cells to the site, dilate cutaneous blood vessels, and cause dermal edema (7). Typically, the resultant swelling is used to quantify the immune response.Matrix metalloproteinases (MMPs) are a family of zinccontaining, extracellular, matrix-degrading enzymes that share common structural and functional properties (8). There are 14 well characterized human MMPs: three collagenases, three stromelysins, two gelatinases, metalloelastase, matrilysin, and four cell-associated or ''membrane-type'' MMPs. Immune cells, including T cells, Langerhans cells, and macrophages, produce MMPs such as stromelysin-1 and gelatinase B. Stromelysin-1 has broad substrate specificity, attacking laminin, collagen IV, fibronectin, entactin, and proteoglycans (9). Gelatinase B (MMP-9) is highly efficient in the cleavage o...

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Contact-Sensitizing and Tolerogenic Properties of 2,4-Dinitrothiocyanobenzene

Cited by 22 publications

References 9 publications

Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance and Sensitization

Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance and Sensitization

The Cutaneous Biochemical Redox Barrier: A Component of the Innate Immune Defenses against Sensitization by Highly Reactive Environmental Xenobiotics

Matrix metalloproteinase deficiencies affect contact hypersensitivity: Stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response

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