Chronic Contact Hypersensitivity Research Articles

119 Noncanonical NF-κB signaling is essential for development of chronic contact hypersensitivity (CHS)

119 Noncanonical NF-κB signaling is essential for development of chronic contact hypersensitivity (CHS)

IL-25 contributes to development of chronic contact dermatitis in C57BL/6 mice, but not BALB/c mice

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25−/−) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice.

576 Difamilast, a new topical PDE4 inhibitor, ameliorates not only chronic allergic dermatitis but also idiopathic dermatitis induced by psychological stress in mice

Difamilast is a novel PDE4 inhibitor with the strongest inhibitory activity against PDE4B among the four PDE4 subtypes. Moizerto® ointment (0.3%, 1% difamilast) has been recently approved for treatment of atopic dermatitis (AD) in Japan. Exogenous antigen stimulation or psychological stress can trigger or exacerbate AD symptoms. In this study, we evaluated the therapeutic effects of difamilast, tacrolimus, and betamethasone valerate on two different mice models of dermatitis: one was chronic contact hypersensitivity (CCH) induced by repeated application of hapten every 2 days for 52 days, the other was idiopathic dermatitis due to persistent self-scratching induced by application of hapten three times a week for 16 weeks, followed by individual housing (social isolation) for 6 months. Efficacy was assessed by repeated topical application of each drug for 4 or 6 weeks after each dermatitis established. In the CCH model, difamilast ointment group significantly improved skin hyperplasia from 0.03% to 3% dose-responsibly with inhibition of inflammatory cell infiltration such as T cells, eosinophils, and neutrophils. Betamethasone valerate ointment (0.12%) improved skin hyperplasia more strongly than 3% difamilast ointment. Tacrolimus ointment (0.1%) temporarily improved skin symptoms, but eventually had no effect. In the idiopathic dermatitis model, difamilast (1%, 3%) significantly improved skin symptoms with a decrease in MIP-1 alpha and MIP-2 content. Tacrolimus (0.1%) slightly improved skin symptoms, while betamethasone valerate (0.1%) exacerbated it. Notably, difamilast ameliorates both CCH and psychological stress-induced idiopathic dermatitis. Betamethasone valerate worsened the idiopathic dermatitis probably due to skin atrophy as steroid’s side effect and tacrolimus had weak effects in both models. Therefore, difamilast is expected to be a possible treatment for AD symptoms such as chronic allergic dermatitis and psychological stress-exacerbated idiopathic dermatitis.

Perspective of delayed Hypersensitivity: A review

T cells enter tissues and are activated by antigen-presenting cells to produce cytokines that cause inflammation in the local area. In allergic contact dermatitis, drug eruptions, asthma, and autoimmune disorders, CD8+ T lymphocytes mediate DTH reactions. As an example of this type IV hypersensitivity, chronic DTH reactions, contact hypersensitivity, and hypersensitivity pneumonitis are all examples. Infiltration of an antigen-exposed region by Th1 cells and macrophages, which inflict tissue damage, is the primary cause of the delayed onset of symptoms. It has thus been outlined that this delayed hypersensitivity reaction.

Central, but not peripheral, nervous system ERK2 is essential for itch signals in murine allergic skin inflammation.

Itch is a common cutaneous symptom in a variety of dermatological diseases, but detailed neuropathological mechanisms remain to be fully elucidated. This study aimed to assess in vivo ERK2 functions in the nervous system for itch responses. We generated conditional knockout mice deficient in ERK2 of the central nervous system (CNS) or peripheral nervous system (PNS), respectively, and assessed chemical and mechanical itch responses in vivo. Chemical itch responses to histamine, but not to BAM8-22, were alleviated in CNS Erk2-deficient mice. In contrast, both histamine- and BAM8-22-induced mechanical itch (alloknesis) were alleviated in CNS Erk2-deficient mice. Neither chemical itch nor mechanical itch induced by these pruritogens was affected by PNS ERK2 deficiency. Spontaneous scratching behaviors during acute and chronic contact hypersensitivity were impaired in CNS Erk2-deficient mice, but not PNS Erk2-deficient mice. In addition, CNS ERK2 deficiency attenuated mechanical itch responses during chronic contact hypersensitivity. Again, PNS Erk2-deficient mice showed comparable responses of mechanical itch to control mice. In addition, alleviated mechanical itch in CNS Erk2-deficient mice was observed in IgE-mediated prurigo-like allergic skin inflammation. Mechanical itch induced by IL-31 was also alleviated by CNS ERK2 deficiency. Phosphorylated ERK1/2 was detected in neurokinin B-expressing cells of the spinal dorsal horn of control mice; these cells accumulated during the induction of chronic contact hypersensitivity. Notably, phosphorylated ERK1/2 was also localized in spinal urocortin3-expressing neurons that are known to transmit mechanical itch. Spinal cord ERK2 could be a potential therapeutic target for intractable itch in pruritic skin diseases.

Anti-inflammatory mechanism of Nrf2-ARE activator in chronic contact hypersensitivity model mice

Anti-inflammatory mechanism of Nrf2-ARE activator in chronic contact hypersensitivity model mice

Effects of 2′-3′-dihydroxy-4′,6′-dimethoxychalcone derived from green perilla on auricle thickness in chronic contact dermatitis model mice

Oxidative stress has been implicated in the pathogenesis of allergic contact dermatitis. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, an in vivo antioxidant system, induces antioxidant enzymes. In our previous studies, we isolated 2ʹ,3ʹ-dihydroxy-4ʹ,6ʹ-dimethoxychalcone (DDC) from green perilla and identified it as a novel activator of the Nrf2-ARE pathway. We also discovered that it exerted cytoprotective effects against oxidative stress in PC12 cells. However, its effects on skin disease model animals in vivo remain unclear. In the present study, auricular thickness time-dependently increased with the repeated application of picryl chloride, and significant increases were observed from Day 2 in chronic contact hypersensitivity (cCHS) model mice. Histological changes, such as higher numbers of cells in the epidermis, were observed with increases in auricular thickness. The administration of DDC every two days from Day 6 suppressed the increases in auricular thickness and the number of scratching events in a dose-dependent manner. The expression levels of antioxidant enzymes increased in the mouse auricle 24 h after the administration of DDC. These results presume that DDC inhibits increases in auricular thickness in cCHS mice by up-regulating the expression of antioxidative enzymes through the activation of the Nrf2-ARE pathway.

Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite of a Th2-favoured humoral response

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common skin inflammatory conditions. B and T cells are strongly implicated in allergic contact hypersensitivity (CHS) conditions. Activation of IgD B-cell receptor (BCR) by anti-IgD stimulation depletes mature B cells and modulates T-helper cell type 1/2 (Th1/2) responses in vivo. It is not known whether these effects by anti-IgD exacerbates or ameliorates chronic skin inflammations. This study investigated the effects of anti-IgD and B-cell depleting anti-CD20 antibody on skin inflammation in CHS murine models. Chronic CHS were induced by challenges with allergens trimellitic anhydride (TMA) or 2,4 dinitrochlorobenzene (DNCB). Mice were treated with an anti-IgD or anti-CD20 at various time-points following allergen challenges. This study revealed that early therapeutic treatments with anti-IgD at 4 h after allergen challenge significantly reduced skin inflammation in both TMA- and DNCB-induced CHS models (P < 0.05). In contrast, anti-CD20 treatment exacerbated skin inflammation in DNCB-induced CHS despite of an extensive B cell depletion (P < 0.05). Anti-IgD treatment depleted mature CD19+IgD+ B cells but enhanced allergen-specific IgM and total IgE productions, suggesting a Th2-favoured humoral response. Anti-IgD reduced neutrophilic infiltrations but increases accumulation of mast cells in dermal tissues. The anti-inflammatory effects of anti-IgD were supported by evidence of an increase in the percentage of regulatory B cells and T cells. Collectively, this study demonstrates that immune-modulation by anti-IgD treatment suppresses Th2-mediated allergic skin inflammation in murine models despite a skew toward a Th2-favvoured humoral response and therefore may present a novel treatment for chronic human AD and ACD.

The role of toll-like receptor 3 in chronic contact hypersensitivity induced by repeated elicitation

BackgroundAccumulating evidence suggests that Toll-like receptor (TLR)-3 signaling is involved in non-infectious immune and inflammatory reactions as well as in viral infections. The skin of patients with atopic dermatitis (AD) is often infected with virus and bacteria, leading to the aggravation of atopic symptoms. These findings suggest TLR3 signaling may be involved in the pathogenesis of AD, but the exact role of TLR3 in AD remains to be defined. ObjectiveThe purpose of this study was to investigate the role of TLR3 in chronic contact hypersensitivity reactions induced by repeated elicitation, resembling the features of AD. MethodsWild-type (WT) and Toll-like receptor 3 knockout (Tlr3 KO) mice were sensitized, and chronic contact hypersensitivity reactions were elicited in their ear skin via repeated application of a hapten, 2,4,6-trinitro-1-chlorobenzene (TNCB) or oxazolone. ResultsThe Tlr3 KO mice exhibited less ear swelling, less leukocyte infiltration into the skin, and lower serum total IgE levels than WT mice after hapten challenge. The Tlr3 KO mice also displayed lower expression levels of inflammatory cytokines (interleukin (IL)-33, IL-4, IL-10, and interferon-ɤ in their TNCB-treated ear skin than WT mice. ConclusionThese results showed that TLR3 deficiency suppressed the development of chronic contact hypersensitivity reactions, suggesting that TLR3 signaling may participate in the pathogenesis of AD.

Toll-like receptor 3 increases chronic contact hypersensitivity induced by repeated application of hapten

Toll-like receptor 3 increases chronic contact hypersensitivity induced by repeated application of hapten

Repeated application of different types of hapten drives immunologically distinct chronic contact hypersensitivity

Repeated application of different types of hapten drives immunologically distinct chronic contact hypersensitivity

Contact allergy in the population of patients with chronic inflammatory dermatoses and contact hypersensitivity to corticosteroids.

IntroductionClinical studies indicate that contact allergy to glucocorticosteroids (GCS) is not rare and has been increasingly reported over the past decade. Among the risk factors for developing contact hypersensitivity to topical corticosteroids, chronic inflammatory skin diseases and polyvalent contact allergy seem to be most important.AimTo present the structure of contact allergy in the population of patients with chronic inflammatory dermatoses (CID) and contact hypersensitivity to corticosteroids.Material and methodsTwenty-seven patients with contact allergy to GCS and chronic inflammatory dermatoses were patch tested with 28 European Baseline Series allergens and 8 corticosteroid allergens. This study group consisted of 5 patients with atopic dermatitis (AD), 15 patients with contact eczema (CE) and 7 with chronic leg eczema (CLE). Nineteen (70.4%) patients were females and 8 (29.6%) were males.ResultsIn the study group, the most sensitizing non-steroidal allergens were nickel sulfate (51.8%), cobalt chloride (33.3%) and balsam of Peru (29.6%). The most sensitizing corticosteroid allergens were budesonide (77.8%), betamethasone valerate and clobetasol propionate (55.5% each). A total of 77.8% of patients allergic to GCS also showed sensitivity to at least one non-steroidal allergen from the European Baseline Series.ConclusionsThe most important risk factors for developing contact allergy to corticosteroids appear to be chronic inflammatory dermatoses, long disease duration, extended on-and-off topical corticosteroid use, patients presenting two or more positive patch test results and polyvalent contact allergy to metal salts and to other non-steroidal haptens.

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient KitW-sh/W-sh (Sash) and MCPT5-Cre+iDTR+ mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8+ tissue-resident memory T (TRM) cells. The CD8+ T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8+ TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.

Estrogen inhibits acute and chronic contact hypersensitivity response in mice

Estrogen inhibits acute and chronic contact hypersensitivity response in mice

446 In vivo dynamics of reactive oxygen species (ROS) and NF-kB activation during acute and chronic contact hypersensitivity reaction (CHSR)

446 In vivo dynamics of reactive oxygen species (ROS) and NF-kB activation during acute and chronic contact hypersensitivity reaction (CHSR)

보중익기탕(補中益氣湯)이 접촉성 과민반응에 미치는 영향(影響)

Objective : The water extract of Bojungikgi-tang (BTE) composed with Ginseng Radix, Astragali Radix, Angelicae gigantis Radix, Atractylodes Rhizoma alba, Aurantii nobilis Pericarpium, Glycyrrhizae Radix, Cimicifuga Rhizoma, and Bupleuri Radix and it has been traditionally used for chronic diseases or weakness after illness in oriental countries. However, little is known about the effects of aqueous extract of BTE on trimellitic anhydride (TMA)-induced contact hypersensitivity (CHS). Therefore, the aim of this study was to investigate the effects of BTE on TMA-induced CHS in BALB/c mice.Methods : In this study, the extract of BTE was prepared by extracting with distilled water at 100℃ for 2.5 h. The extract was freeze-dried following filtration through 0.45 μm filter. Mice were orally administrated with or without BTE extract of different doses (25-200 ㎎/㎏/day) for 28 days. During the challenge period, mice were externally applied with different doses of BTE extract one time per day 30 min before TMA treatment. I examined the effects of BTE on the serum levels of IgE, IgG1, IgG2a, and IgG2b, nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in isolated peritoneal macrophages, Th2 cytokine production in isolated spleen cells, ear swelling responses, and the leukocyte infiltration induced by TMA.Results : The orally and externally administration of BTE dose-dependently reduced the serum levels of hapten-specific immunoglobulin E (IgE), IgG1 titer, and PGE₂ production as well as ear swelling responses and leukocyte infiltration in TMA-induced BALB/c mice. The levels of NO and PGE₂ production from peritoneal macrophages stimulated with TMA-BSA were markedly suppressed by pretreatment with BTE in a concentration dependent manner. Furthermore, the levels of Th2 cytokines (IL-4, IL-5, IL-13) production from spleen cells stimulated with ConA were markedly suppressed by BTE treatment in a concentration dependent manner.Conclusions : These results suggest that BTE treatment suppresses chronic contact hypersensitivity, and it can be assumed that the suppression of ear swelling, serum IgE, NO and PGE₂ levels, leukocyte infiltration, and Th2 cytokines in an animal model. Therefore, these properties may contribute to the strong anti-CHS response effect of BTE.

Chronic Toxoplasmosis Modulates the Induction of Contact Hypersensitivity by TNCB in Mouse Model.

Mouse models of chronic toxoplasmosis and atopic dermatitis (AD) were combined to clarify the effect of opportunistic Toxoplasma gondii infection on the development of AD. AD was induced as a chronic contact hypersensitivity (CHS) with repeated challenge of 2,4,6-trinitro-1-chlorobenzene (TNCB) on the dorsal skin of mice. TNCB induced skin thickness increases in both normal and toxoplasmic mice. The changing patterns were different from the sigmoidal which saturated at 20 days in normal mice to the convex saturated at 12 days in toxoplasmic mice with the crossing at 18 days. Compared to normal mice, toxoplasmic mice presented CHS more severely in earlier times and then moderately in later times. These data suggest that host immune modification by T. gondii infection enhances CHS in early times of atopic stimulation but soothes the reaction of CHS in later times in mouse model.

In vivo optical imaging of matrix metalloproteinase activity detects acute and chronic contact hypersensitivity reactions and enables monitoring of the antiinflammatory effects of N-acetylcysteine.

The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.

The VEGF-C/VEGFR3 signaling pathway contributes to resolving chronic skin inflammation by activating lymphatic vessel function

BackgroundThe functions of lymphatic vessels are to drain the protein-rich lymph from the extracellular space, to maintain normal tissue pressure, and to mediate the immune response, particularly in inflammatory conditions. ObjectiveTo evaluate the function of the vascular endothelial growth factor (VEGF)-C/VEGF receptor (VEGFR)-3 signaling pathway in chronic skin inflammation. MethodsWe used adenovirus-mediated VEGF-C or VEGFR3-immunoglobulin (Ig) production and investigated the effects of VEGF-C/VEGFR3 signaling on the resolution of inflammation using the experimental chronic contact hypersensitivity (CHS) reaction mouse model. ResultsVEGF-C gene transfer promoted significant reduction of ear swelling and ear weight in CHS reaction-induced skin inflammation. Although, there was no significant difference in the number of lymphatic vessels, the number of infiltrating CD11b-positive inflammatory cells was significantly reduced in the VEGF-C group, which suggested that VEGF-C upregulated the drainage of interstitial fluid and inflammatory cells via lymphatic vessels. Furthermore, blockade of VEGFR3 expression resulted in a significant delay in the recovery from CHS reaction-induced skin inflammation. Lymphatic vessel size was enlarged and a significant increase of infiltrating CD11b inflammatory cells was observed in mice with VEGFR3-Ig gene transfer compared to control mice. These results suggested that blockade of VEGFR3 inhibited the drainage function of the lymphatic system. ConclusionThis study provides evidence that VEGF-C/VEGFR3 signaling plays an important role in the resolution of skin inflammation; the regulation of lymphatic function may have a great therapeutic potential in inflammatory skin diseases.

Distinct roles of prostaglandin D2 receptors in chronic skin inflammation

Prostaglandin D2 (PGD2) is a prostanoid implicated in allergic inflammation. However, the roles of PGD2 in immune and allergic responses remain controversial. PGD2 exerts its effect through the CRTH2 and DP receptors. To elucidate functional differences of PGD2 and its receptors in chronic skin inflammation, chronic contact hypersensitivity (chronic CHS) and IgE-mediated chronic allergic skin inflammation (IgE-CAI) were induced in mice deficient in the CRTH2 and/or DP genes. DP (−/−) mice and CRTH2 (−/−)/DP (−/−) mice showed exacerbated chronic CHS, and conversely, CRTH2 (−/−) mice exhibited diminished skin responses. Skin responses correlated with local levels of IL-13, CCL11, and CCL22. These phenotypic changes in chronic CHS of mutant mice were similar to those in acute CHS despite the differences in the cytokine milieus; chronic CHS and acute CHS were mediated by Th2 and Th1/Th17 immunity, respectively. However, in IgE-CAI, DP (−/−) mice showed comparable skin responses to wild-type mice. Alleviation of IgE-CAI was observed in CRTH2 (−/−) mice, and as a consequence, CRTH2 (−/−)/DP (−/−) mice exhibited diminished IgE-CAI compared with wild-type mice. IgE-CAI in mutant mice correlated with local IL-4 and CCL22 production. Consistent with these results, a CRTH2-specific antagonist exerted inhibitory effects in both chronic CHS and IgE-CAI. The present study demonstrates that functional roles of PGD2 and its receptors appear to depend on the nature of the inflammation. Nevertheless, tools targeted against PGD2-CRTH2 signals could offer therapeutic potential for both types of chronic skin inflammation.