Chisa Nakashima

Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression.

BACKGROUND Nonsense mutations in filaggrin (FLG) represent a significant genetic factor in the cause of atopic dermatitis (AD). OBJECTIVE It is of great importance to find drug candidates that upregulate FLG expression and to determine whether increased FLG expression controls the development of AD. METHODS We screened a library of bioactives by using an FLG reporter assay to find candidates that promoted FLG mRNA expression using a human immortalized keratinocyte cell line (HaCaT). We studied the effect of the compound on keratinocytes using the human skin equivalent model. We examined the effect of the compound on AD-like skin inflammation in NC/Nga mice. RESULTS JTC801 promoted FLG mRNA and protein expression in both HaCaT and normal human epidermal keratinocytes. Intriguingly, JTC801 promoted the mRNA and protein expression levels of FLG but not the mRNA levels of other makers for keratinocyte differentiation, including loricrin, keratin 10, and transglutaminase 1, in a human skin equivalent model. In addition, oral administration of JTC801 promoted the protein level of Flg and suppressed the development of AD-like skin inflammation in NC/Nga mice. CONCLUSION This is the first observation that the compound, which increased FLG expression in human and murine keratinocytes, attenuated the development of AD-like skin inflammation in mice. Our findings provide evidence that modulation of FLG expression can be a novel therapeutic target for AD.

Natural killer T cells are essential for the development of contact hypersensitivity in BALB/c mice.

Contact hypersensitivity (CHS) has been widely used to study cutaneous immune responses, as a prototype of delayed-type hypersensitivity. Although natural killer T (NKT) cells have been assumed to have an important role in CHS, their role is controversial. Here, we report the role of NKT cells in the sensitization phase of CHS, by promoting the survival and maturation of dendritic cells (DCs) in the draining lymph nodes (LNs). The CHS response was attenuated with Cd1d1(-/-) and Traj18(-/-) BALB/c mice in which NKT cells were absent. In the draining LNs, the number of effector T cells and cytokine production were significantly reduced with NKT cell-deficient mice. NKT cells activated and colocalized with DCs in the draining LNs after sensitization. The number of migrated and mature DCs was reduced in NKT cell-deficient mice 72 hours after FITC application. In in vitro experiments, activated NKT cells enhanced bone marrow-derived DC (BMDC) survivability via tumor necrosis factor (TNF) production from BMDCs. In addition, TNF production from BMDCs was partially suppressed by the neutralizing anti-CD54 or CD154 antibodies. Our data demonstrate that DC-NKT interaction has a pivotal role in the sensitization phase of CHS.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients

ABSTRACT Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+ T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+ T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+ T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus

Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.

Treatment of intractable oral lichen planus with intravenous immunoglobulin therapy

ejd.2012.1827 Auteur(s) : Chisa Nakashima otsukamn@kuhp.kyoto-u.ac.jp, Atsushi Otsuka, Hiroko Sonobe, Akihiko Kitoh, Mayumi Kato, Satoshi Kore-Eda, Yoshiki Miyachi, Kenji Kabashima Department of Dermatology, Kyoto University School of Medicine, 54 Shogoin-Kawara Sakyo, Kyoto 606-8507, Japan Lichen planus (LP) is a chronic dermatosis and is idiopathic or associated with underlying systemic diseases, such as hepatitis C virus [1]. LP can involve skin, genital mucosa, hair follicles, and nails. In [...]

Biomarkers for evaluation of mast cell and basophil activation

Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.

Interleukin‐31 and interleukin‐31 receptor–new therapeutic targets for atopic dermatitis

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell‐mediated immunity. Interleukin (IL)‐31 is a potent pruritogenic cytokine primarily produced by Th2 cells. Both IL‐31 transgenic mice and wild‐type mice treated with IL‐31 exhibit AD‐like skin lesions and scratching behaviour. IL‐31 receptor α‐chain (IL‐31RA) is also expressed in peripheral nerves and epidermal keratinocytes, and the roles of IL‐31 on pruritus and skin barrier have been investigated. Recently, an anti–IL‐31 receptor antibody was shown to significantly improve pruritus in AD patients. This review focuses on IL‐31 and IL‐31RA in AD.

Pellagra-like erythema on sun-exposed skin of patients with anorexia nervosa

the anterior neck was suggestive of Casal’s necklace, characteristic of this disease. We could considerer dermatomyositis as the patient had a polymyositis for years, but the clinical picture, namely the absence of heliotrope rash, Gottron papules, periungual telangiectasias or cuticular changes ruled out that diagnosis. The patient also had diarrhea, which in addition to the cutaneous findings and the low level of vitamin B3 contributed to the diagnosis of pellagra. Additional testing precluded other diagnoses, namely photo-dermatoses such as lupus erythematosus and porphyria. We believe that azathioprine was the cause of pellagra, taking into account that it was the only medication that is known to interfere in the niacin pathway. We also excluded the other causes for pellagra. This patient also experienced another side-effect of azathioprine – medullary aplasia – which was the foremost condition contributing to death. Though very rare, there are reported cases of pancytopenia after years of treatment with azathioprine. Aside from the presence of malnutrition and chronic alcoholism, pellagra must be recognized in other clinical settings, namely when drugs interfering with niacin metabolism are present. It is an easily treated condition if timely recognized.

Decrease of superficial serine and lactate in the stratum corneum due to repetitive frictional trauma

Repetitive frictional trauma can be induced in daily and occupational activities, such as daily ablutions with washcloths. The influence of frictional trauma on the skin barrier function, especially in the perspective of the components of stratum corneum (SC), has not yet been studied in detail. Raman spectroscopy is a noninvasive optical technique based on inelastic light scattering that is capable of measuring several components in the skin. In this study, we used Raman spectroscopy to investigate the change in natural moisturizing factor (NMF) components in the SC following repetitive physical friction.