IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.

CD4+ T cells have been shown to play a critical role in the maintenance of an effective anti-viral CD8+ CTL response in murine models. Recent studies have demonstrated that CD4+ T cells provide help to CTLs through ligation of the CD40 receptor on dendritic cells. The role of CD4+ T cell help in the expansion of virus-specific CD8+ memory T cell responses was examined in normal volunteers recently vaccinated to influenza and in HIV-1 infected individuals. In recently vaccinated normal volunteers, CD4+ T cell help was required for optimal in vitro expansion of influenza-specific CTL responses. Also, CD40 ligand trimer (CD40LT) enhanced CTL responses and was able to completely substitute for CD4+ T cell help in PBMCs from normal volunteers. In HIV-1 infection, CD4+ T cell help was required for optimal expansion of HIV-1-specific memory CTL in vitro in 9 of 10 patients. CD40LT could enhance CTL in the absence of CD4+ T cell help in the majority of patients; however, the degree of enhancement of CTL responses was variable such that, in some patients, CD40LT could not completely substitute for CD4+ T cell help. In those HIV-1-infected patients who demonstrated poor responses to CD40LT, a dysfunction in circulating CD8+ memory T cells was demonstrated, which was reversed by the addition of cytokines including IL-2. Finally, it was demonstrated that IL-15 produced by CD40LT-stimulated dendritic cells may be an additional mechanism by which CD40LT induces the expansion of memory CTL in CD4+ T cell-depleted conditions, where IL-2 is lacking.

BackgroundAssociations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early-life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD).MethodsIn utero and early-life vitamin D deficiency was achieved using a vitamin D-deficient diet for female mice during the third trimester of pregnancy and lactation. Offspring were weaned onto a vitamin D-deficient or vitamin D-replete diet, and exposure to intranasal house dust mite (HDM) or saline was commenced from day 3 of life for up to 6 weeks, when airway hyper-responsiveness (AHR), airway inflammation and remodelling were assessed.ResultsNeonatal mice that had in utero and early-life vitamin D deficiency had significantly increased pulmonary CD3+CD4+T1ST2+ cells and reduced CD4+IL-10+ cells. This effect was enhanced following HDM exposure. AHR in HDM-exposed mice was unaffected by vitamin D status. Introduction of vitamin D into the diet at weaning resulted in a significant reduction in serum IgE levels, reduced pulmonary eosinophilia and peri-bronchiolar collagen deposition.ConclusionPeri-natal vitamin D deficiency alone has immunomodulatory effects including Th2 skewing and reduced IL-10-secreting T regulatory cells, exaggerated with additional allergen exposure. Vitamin D deficiency in early life does not affect AHR, but contributes to disease severity with worse eosinophilic inflammation and airway remodelling. Importantly, supplementation with vitamin D improves both of these pathological abnormalities.

Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or ] exposure from day 3 of life resulted in significantly increased pulmonary IL-13CD4 T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinCD45CD90IL-13 type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4IL-13 KO mice (lacking IL-13CD4 T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13 ILCs. Moreover, neonatal mice were protected from AHR when inhaled (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. blocked the expansion of pulmonary IL-13CD4 T cells, whereas IL-13 ILCs and IL-33 remained elevated. Administration of mirrored the findings from the CD4IL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13CD4 T cells, rather than IL-13 ILCs or IL-33, are critical for inception of allergic AHR in early life.

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There is not enough evidence available to guide wound care management in patients with Stevens-Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN). Current guidelines are based on expert opinion and mimic burn wound treatments, including the use of silverimpregnated dressings. Silver-containing dressings reduce the risk of invasive infection by minimizing the bacterial colonization of wounds. Evidence from small clinical trials in burn patients and a retrospective study in SJS/TEN patients indicate that they offer the advantage of not requiring daily dressing changes, which may damage the healing epidermis, and minimize patient discomfort. However, cytotoxic effects of silver have been demonstrated in human cell lines, including leukocytes. Studies investigating silver absorption from silvercoated dressings in burn patients have yielded conflicting results, with only a few case reports warning against the use of silver due to its cytotoxic effects. Systemic silver absorption in patients with SJS/TEN treated with any type of silver-based dressing has not been addressed in previous studies. We performed a retrospective chart review to investigate silver absorption in SJS/TEN patients treated with silver-nylon and silver-foam dressings. Six patients met inclusion/exclusion criteria, with body surface area (BSA) involvement of 75 % -100% and 5 to 25 % denuded skin. Five patients had elevated serum silver levels in the range of 9.9 to 110 ug/l, and had a decrease in leukocyte counts compared to baseline. The patient with normal serum silver levels had normal leukocyte counts, but developed transaminitis. None of the patients developed argyria. Our study indicates that silver-nylon and silver-foam dressings used in patients with SJS/TEN lead to systemic silver absorption. Whether the observed leukopenia and transaminitis are a result of either silver toxicity, the underlying hematological malignancy (3 patients), or SJS/TEN itself, our observations support the need to further investigate the safety of silver-based dressings in patients with SJS/TEN.

Background:We have shown that children with severe therapy resistant asthma (STRA) have airway eosinophilia despite the absence of T helper (Th)2 cytokines (IL-4, IL-5 and IL-13) (Bossley C et al J Allergy Clin Immunol In Press). The mechanism of airway eosinophilia is as yet unknown. Innate cytokines including IL-33 are postulated to initiate disease in adults by release of IL-13 via innate helper cells, but their role in paediatric asthma is unknown. We used a neonatal mouse model and a paediatric asthma cohort to investigate the hypothesis that although IL-33 and IL-13 are important for disease initiation, IL-33 is sufficient to maintain airway hyperresponsiveness (AHR). Methods: Neonatal mice were challenged with intra-nasal house dust mite (HDM) from postnatal day 3 for up to 6 weeks. Levels of IL-13 and IL-33 were assessed. Subsequently cellular expression of IL-33 and IL-13 was quantified in endobronchial biopsies from school aged children with STRA. Dual staining for macrophages (CD68) and IL-33 was also performed. IL-13 was neutralised in the neonatal mouse model before and after disease was established, and assessments of lung function, airway inflammation and remodelling were made. Results: There was an inverse relationship between IL-13 and IL-33 in HDM exposed neonatal mice, whereby IL-13 had increased by week 1 after allergen challenge, peaked at week 2, and subsequently declined and plateaued from week 4 onwards. IL-33 was significantly higher at week 2, and continued to increase with age and allergen exposure to week 6. Tissue IL-13 expression was similar in asthmatic children and age matched controls. However, submucosal IL-33 expression was significantly increased in STRA children compared to controls (median 96 [IQR 39-168] vs 37 [1-85] positive cells/mm , p<0.01). Dual staining confirmed macrophages as the source of IL-33.2

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