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McFadden J.P.,St Johns Institute Of Dermatology | Puangpet P.,St Johns Institute Of Dermatology | Basketter D.A.,DABMEB Consultancy Ltd. | Dearman R.J.,University of Manchester | Kimber I.,University of Manchester
British Journal of Dermatology

The skin immune system's propensity to produce allergic contact dermatitis (ACD) to harmless chemicals, while otherwise being an efficient defence system, represents a dermatological paradox. We postulate that a major role in signalling in ACD is played by Toll-like receptor (TLR)2 and TLR4, and arises from their activation by extracellular danger-associated molecular patterns (DAMPs). Ligand activation of TLR4/2 results in the expression of interleukins (ILs) IL-1β, IL-6, IL-12, IL-18 and IL-23, tumour necrosis factor-α and interferon-α. These cytokines promote acquisition of sensitization, and facilitate elicitation of contact allergy via multiple mechanisms, including the recruitment of CD4+ Th1 and Th17 cells. As Th1 cells secrete large amounts of DAMPs, a DAMP immune circuit (positive-feedback loop) is created. This is an important driver of skin sensitization and skin inflammation. Pathogenic extracellular bacteria, but not commensal bacteria, produce pathogen-associated molecular pattern molecules, which stimulate the expression of Th1- and Th17-promoting cytokines via TLR2 and TLR4. This also induces an immune circuit. The ability of the skin immune system to activate host defence mechanisms and to distinguish between pathogenic bacteria and commensals provides an explanation for why skin sensitization and ACD develop, as they are processes that rely on the same biological pathways. These pathways may also shed light on the pathogenesis of chronic pustular inflammatory dermatoses (e.g. acne vulgaris). The existence of safety signals from commensal bacteria, which prevent initiation of these pathways, may provide opportunities for novel therapeutic approaches to the treatment of inflammatory skin diseases. © 2013 The Authors. BJD © 2013 British Association of Dermatologists. Source

Basketter D.,DABMEB Consultancy Ltd. | Kimber I.,University of Manchester
Regulatory Toxicology and Pharmacology

The identification, characterisation, risk assessment and risk management of materials that cause allergic sensitisation is an important requirement for human health protection. It has been proposed that for some chemical and protein allergens, and in particular for those that cause sensitisation of the respiratory tract (associated with occupational asthma), it may be appropriate to regard them as Substances of Very High Concern (SVHC) under the provisions of REACH (Registration, Evaluation, Authorisation and restriction of CHemicals). We have argued previously that categorisation of sensitising agents as SVHC should be used only in exceptional circumstances. In the present article, the subject of SVHC is addressed from another perspective. Here the information that would be required to provide a compelling case for categorisation of a skin sensitising substance as a SVHC is considered. Three skin sensitising chemicals have been identified to serve as working examples. These are chromate, a potent contact allergen, and the skin sensitisers formaldehyde and isoeugenol. The key criterion influencing the decision regarding a skin sensitiser being categorised as SVHC is the extent to which impacts on the quality of life are reversible. Consequently, SVHC categorisation for skin sensitising chemicals should be used only in exceptional circumstances. © 2014 Elsevier Inc. Source

Kimber I.,University of Manchester | Basketter D.A.,DABMEB Consultancy Ltd.
Regulatory Toxicology and Pharmacology

Characterisation of the relative sensitizing potency of protein and chemical allergens remains challenging, particularly for materials causing allergic sensitization of the respiratory tract. There nevertheless remains an appetite, for priority setting and risk management, to develop paradigms that distinguish between individual respiratory allergens according to perceptions of the hazards and risks posed to human health. One manifestation thereof is recent listing of certain respiratory allergens as Substances of Very High Concern (SVHC) under the provisions of REACH (Registration, Evaluation, Authorisation and restriction of Chemicals). Although priority setting is a laudable ambition, it is important the process is predicated on evidence-based criteria that are transparent, understood and owned. The danger is that in the absence of rigorous criteria unwanted precedents can be created, and confidence in the process is compromised. A default categorisation of sensitisers as SVHC requiring assessment under the authorisation process is not desirable. We therefore consider here the value and limitations of selective assignment of certain respiratory allergens as being SVHC. The difficulties of sustaining such designations in a sound and equitable way is discussed in the context of the challenges that exist with respect to assessment of potency, and information available regarding the effectiveness of exposure-based risk management. © 2014 Elsevier Inc. Source

McFadden J.P.,Kings College | Thyssen J.P.,Gentofte University Hospital | Basketter D.A.,DABMEB Consultancy Ltd. | Puangpet P.,Institute of Dermatology | Kimber I.,University of Manchester
British Journal of Dermatology

During the last 50 years there has been a significant increase in Western societies of atopic disease and associated allergy. The balance between functional subpopulations of T helper cells (Th) determines the quality of the immune response provoked by antigen. One such subpopulation - Th2 cells - is associated with the production of IgE antibody and atopic allergy, whereas, Th1 cells antagonize IgE responses and the development of allergic disease. In seeking to provide a mechanistic basis for this increased prevalence of allergic disease, one proposal has been the 'hygiene hypothesis', which argues that in Westernized societies reduced exposure during early childhood to pathogenic microorganisms favours the development of atopic allergy. Pregnancy is normally associated with Th2 skewing, which persists for some months in the neonate before Th1/Th2 realignment occurs. In this review, we consider the immunophysiology of Th2 immune skewing during pregnancy. In particular, we explore the possibility that altered and increased patterns of exposure to certain chemicals have served to accentuate this normal Th2 skewing and therefore further promote the persistence of a Th2 bias in neonates. Furthermore, we propose that the more marked Th2 skewing observed in first pregnancy may, at least in part, explain the higher prevalence of atopic disease and allergy in the first born. © 2014 British Association of Dermatologists. Source

Basketter D.A.,DABMEB Consultancy Ltd. | Kimber I.,University of Manchester
Journal of Applied Toxicology

The advent of the local lymph node assay (LLNA), and efforts to develop in vitro alternatives for the identification of skin sensitizing chemicals has focused attention on the issue of false positive and false negative results. In essence, the question becomes 'what is the gold standard?' In this context, attention has focused primarily on the LLNA as this is now the preferred assay for skin sensitization testing. However, for many years prior to introduction of the LLNA, the guinea pig maximization test and the occluded patch test of Buehler were the methods of choice. In order to encourage a more informed dialogue about the relative performance, accuracy and applicability of the LLNA and guinea pig tests,we have here considered the extent to which guinea pig methods were themselves subject to false positives and negative results. We describe and discuss here well-characterized examples of instances where both false negatives (including abietic acid and eugenol) or false positives (including vanillin and sulfanilic acid) have been recorded in guinea pig tests. These and other examples are discussed with particular reference to the fabrication of a gold standard dataset that is required for the validation of in vitro alternatives. Copyright © 2010 John Wiley & Sons, Ltd. Source

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