Ian Kimber

Cytokine endpoints for the local lymph node assay: consideration of interferon-γ and interleukin 12

The murine local lymph node assay (LLNA) is a method for the prospective identification of contact allergens. Skin sensitization potential is assessed as a function of induced proliferative responses in lymph nodes draining the site of topical exposure measured in situ by incorporation of radiolabelled thymidine ([3H]thymidine). The results of previous investigations have demonstrated that the analysis of [3H]thymidine incorporation represents a robust and reliable endpoint for the LLNA for the assessment of skin sensitizing activity for strong and moderate allergens and, in addition, many weaker sensitizers. The aim of the current experiments was to explore the utility of the production of the cytokines interferon‐γ (IFN‐γ) and interleukin 12 (IL‐12) by draining lymph node cells (LNC) as alternative readouts for the LLNA.

T helper cell 2 immune skewing in pregnancy/early life: chemical exposure and the development of atopic disease and allergy.

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.

Exogenous interleukin-1beta restores impaired Langerhans cell migration in aged skin.

As far as we know this response has not been previously reported. Nodular prurigo is characterized by reduplication of cutaneous peptidergic nerves. Topical tacrolimus reputedly elicits a tingling and burning sensation on topical application. The mechanism is not known but we speculate that there may be a direct capsaicin-like effect on the sensory afferent nerve fibres. Furthermore, this patient’s skin pretreatment showed increased S-100 staining of cutaneous nerves. The quantity and extent of the staining was considerably diminished in a skin biopsy taken after treatment with tacrolimus. However, nodular prurigo is an eczematous condition. Ciclosporin, another calcineurin inhibitor, has been reported to be successful in managing nodular prurigo when administered orally. Both ciclosporin and tacrolimus are known to be efficacious in suppressing proinflammatory cytokines in eczematous inflammatory processes.

Skin sensitization: Implications for integration of clinical data into hazard identification and risk assessment.

Skin sensitization associated with allergic contact dermatitis is a common health problem and is an important consideration for toxicologists in safety assessment. Historically, in vivo predictive tests have been used with good success to identify substances that have the potential to induce skin sensitization, and these tests formed the basis of safety evaluation. These original tests are now being replaced gradually either by in vitro assays or by further refinements of in vivo methods such as the local lymph node assay. Human data have also been available to inform classification decisions for some substances and have been used by risk managers to introduce measures for exposure reduction. However, humans encounter hazards in the context of exposure rather than in the form of intrinsic hazards per se, and so in this article, we have examined critically the extent to which human data have been used to refine classification decisions and safety evaluations. We have also evaluated information on the burden of human allergic skin disease and used this to address the question of whether, and to what extent, the identification and evaluation of skin sensitization hazards has led to an improvement of public and/or occupational health.

Psoriasis and basement-membrane laminin.

1 Kim YH, Jensen RA, Watanabe GL et al. Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 1996; 132:1309–13. 2 Kim YH, Hoppe RT. Mycosis fungoides and the S ezary syndrome. Semin Oncol 1999; 26:276–89. 3 Agar NS, Wedgeworth E, Crichton S et al. Survival outcomes and prognostic factors in mycosis fungoides/S ezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28:4730–9. 4 Quir os PA, Jones GW, Kacinski BM et al. Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 1997; 38:1027–35. 5 Kaye FJ, Bunn PA Jr, Steinberg SM et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989; 321:1784–90. 6 Page V, Gardner A, Karzmark CJ. Patient dosimetry in the electron treatment of large superficial lesions. Radiology 1970; 94:635–41. 7 Rampino M, Ragona R, Monetti U et al. Total skin electron beam therapy in mycosis fungoides. Our experience from 1985 to 1999. Radiol Med 2002; 103:108–14. 8 Duvic M, Apisarnthanarax N, Cohen DS et al. Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 2003; 49:35–49. 9 Reddy S, Parker CM, Shidnia H et al. Total skin electron beam radiation therapy for mycosis fungoides. Am J Clin Oncol 1992; 15:119–24. 10 Roberge D, Muanza T, Blake G et al. Does adjuvant alpha-interferon improve outcome when combined with total skin irradiation for mycosis fungoides? Br J Dermatol 2007; 156:57–61.

Impaired Langerhans cell migration in psoriasis is due to an altered keratinocyte phenotype induced by interleukin‐17

Psoriasis is a common skin condition driven by increased expression of interleukin (IL)‐17. Langerhans cells (LCs) are epidermal dendritic cells that regulate cutaneous immune responses. Within the uninvolved skin of patients with psoriasis, LCs display impaired migration from the epidermis.

Keratinocytes derived from late-onset-psoriasis skin do not impair Langerhans cell migration

Chronic plaque psoriasis (CPP) is associated with over-expression of interleukin (IL)-17 and systemic antibody therapies targeting this cytokine are highly efficacious1 . Psoriasis presents as either early- or late-onset disease (before or after 40 years of age, respectively). Langerhans cells (LC) are the dendritic cells of the epidermis that regulate cutaneous immune responses2 . In the uninvolved skin of early-onset CPP there is impaired LC migration after exposure to a contact allergen, tumour necrosis factor-α (TNF-α) or IL-1β in vivo3 . However, in late-onset psoriasis there is impaired migration in response to TNF-α, but normal responses to IL-1β4 . We have recently shown that in early-onset psoriasis, LC migration is impaired as a result of IL-17A causing changes in the psoriasis keratinocyte secretome5 . Here we sought to examine whether keratinocytes isolated from uninvolved late-onset psoriasis skin also impair LC migration. This article is protected by copyright. All rights reserved.