Wolfgang Bäumer

Histamine H4 receptor antagonism reduces hapten‐induced scratching behaviour but not inflammation

Abstract:  Effects of the histamine H4 receptor antagonist JNJ 7777120 (1‐[(5‐chloro‐1H‐indol‐2‐yl)carbonyl]‐4‐methylpiperazine) were tested in two models of allergic contact dermatitis. Dermatitis was induced by 2,4‐dinitrochlorobenzene and toluene‐2,4‐diisocyanate, which differ in their Th1–Th2 profile in that way that 2,4‐dinitrochlorobenzene is a classical contact allergen with a pronounced Th1‐mediated inflammation, while the respiratory chemical allergen toluene‐2,4‐diisocyanate induces a Th2‐dominated inflammation. JNJ 7777120 (15 mg/kg) administered 2 h and 30 min before and 1 h after challenge did not reduce the hapten‐induced ear swelling determined 24 h after challenge. This was confirmed by histological evaluation of the ear skin. A repeated administration of the haptens to the rostral part of the back of sensitized animals resulted in a frequent scratching behaviour. An administration of JNJ 7777120 (15 mg/kg) 30 min before challenge reduced this hapten‐induced scratching significantly. The H1 receptor antagonist cetirizine also reduced the scratching bouts in sensitized mice. A combination of H1 and H4 receptor antagonists resulted in the strongest inhibition of scratching behaviour associated with allergic dermatitis. These results indicate that H4 receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergen‐induced itch. Thus, a combination of H4 and H1 receptor antagonism might be a new strategy to treat pruritus related to allergic diseases like atopic dermatitis.

Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis

The phosphodiesterase (PDE) 4 is the predominant cyclic AMP degrading enzyme in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Highly selective PDE4 inhibitors are currently under evaluation for the treatment of asthma and/or chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immuno-modulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as atopic dermatitis. Consequently, PDE4 inhibitors including cilomilast and AWD 12-281 have been tested in several models of allergic and irritant skin inflammation. These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitised guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an anti-inflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis. Results of early clinical trials with both topically (cipamfylline, CP80,633) and systemically (CC-10004) active PDE4 inhibitors demonstrated efficacy in atopic dermatitis and in the case of CC-10004, also in psoriasis. AWD 12-281 (GW 842470) is currently under clinical evaluation for the topical treatment of atopic dermatitis. Results concerning clinical efficacy of this potent and selective PDE4 inhibitor are anxiously awaited.

Histamine H4 receptors modulate dendritic cell migration through skin – immunomodulatory role of histamine

Background:  Dendritic cells (DC) are the major antigen‐presenting cells and play a key role in adaptive immunity as they are able to activate naive T cells. It was recently described, that the histamine H4 receptor (H4R) is present on human monocyte‐derived DC and that chemotaxis and T‐helper (Th)1–Th2 polarization is mediated by this receptor. However, the distribution of histamine receptors on murine DC has not been studied yet.

Murine and human Langerhans cells express a functional histamine H4 receptor: modulation of cell migration and function

To cite this article: Gschwandtner M, Rossbach K, Dijkstra D, Bäumer W, Kietzmann M, Stark H, Werfel T, Gutzmer R. Murine and human Langerhans cells express a functional histamine H4 receptor: modulation of cell migration and function. Allergy 2010; 65: 840–849.

Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration.

Migration of Langerhans cells (LCs) from the skin to the lymph node is an essential step in the pathogenesis of allergic contact dermatitis (ACD). Therefore, inhibition of LC-migration could be a promising strategy to improve this skin disease. Effects of sphingosine-1-phosphate (S1P) and the immunomodulator FTY720 on LC trafficking is not well defined, yet. Thus, we investigated the action of topically administered S1P and FTY720 in a murine model of ACD. Most interestingly, FTY720 as well as S1P inhibited the inflammatory reaction in the elicitation phase of ACD. In the sensitization phase, FTY720, and S1P reduced the weight and cell count of the draining auricular lymph node, as well as immigrated dendritic cells provoked by repetitive topical administration of the hapten. Correspondingly, the density of LCs in the epidermis was higher in FTY720- and S1P-treated mice compared to vehicle treatment. A skin dendritic cell migration assay confirmed the significant inhibition of dendritic cell migration by FTY720 and S1P. These data supply conclusive evidence that the strategy of targeting the migratory response of LCs with locally acting S1P or FTY720 represents an emerging option in the treatment of allergic skin diseases like contact hypersensitivity and atopic dermatitis.

Histamine Upregulates Keratinocyte MMP-9 Production via the Histamine H1 Receptor

Skin inflammation and the migration of cells at the site of the immune response play an important role in allergic skin diseases. It has already been described that matrix metalloproteinase 9 (MMP-9) influences tissue remodeling and facilitates cell migration by proteolytic degradation of basal membrane components. The aim of this study was to investigate MMP-9 expression on human primary keratinocytes (KCs) upon stimulation with histamine, a potent mediator in allergic responses. With ELISA and zymography, we could show that histamine induced dose-dependent upregulation of MMP-9 in cultured KCs and in punch biopsies of human skin. The histamine H(1) receptor (H(1)R) agonist beta-histine-but not agonists for H(2)R, H(3)R, and H(4)R-induced MMP-9, whereas the H(1)R antagonist clemastine blocked the effect in a dose-dependent manner. Immunohistological staining showed that histamine-induced MMP-9 led to destruction of type IV collagen at the basement membrane in healthy skin. In a coculture system of KCs and T cells, migration of T cells through an artificial basement membrane was increased after histamine stimulation of KCs. Our findings demonstrate enhanced MMP-9 production and cell migration after histamine stimulation and may represent a new mechanism by which KCs contribute to the pathology of skin diseases.

Sphingosine 1-phosphate modulates antigen capture by murine Langerhans cells via the S1P2 receptor subtype.

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions.

Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12-281 on the inflammatory reaction in a model of allergic dermatitis.

The inhibitors of the phosphodiesterase 4, SB 207499 (cilomilast, c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-L-cyclohexane carboxylic acid) and AWD 12-281 (N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide) were tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate. The allergic reaction was challenged by topical administration of toluene-2,4-diisocyanate onto the mice ears. Before challenge, two groups of mice were treated topically (ear skin) with SB 207499 or AWD 12-281. There was a significant ear swelling in toluene-2,4-diisocyanate-challenged mice ears 4, 8, 16, 24 and 48 h after challenge. SB 207499 and AWD 12-281 inhibited this swelling significantly 8, 16, 24 and 48 h after the challenge. For biochemical parameters and histology, ears were sampled from mice sacrificed 4, 8 and 16 h after the challenge. In homogenized tissue, SB 207499 and AWD 12-281 inhibited significantly the secretion of interleukin 1beta induced by toluene-2,4-diisocyanate 4 and 8 h after challenge. The cell influx (granulocytes) observed in the toluene-2,4-diisocyanate-challenged mice 8 and 16 h after challenge was nearly abolished by AWD 12-281 and SB 204799.

Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow–derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.

Lack of preventing effect of systemically and topically administered histamine H1 or H4 receptor antagonists in a dog model of acute atopic dermatitis

As there is evidence for an anti‐inflammatory efficacy of histamine H4 receptor (H4R) selective antagonists, we aimed at testing the efficacy of the H4R antagonists JNJ7777120 and JNJ28307474 in comparison with histamine H1 receptor (H1R) antagonists hydroxyzine and cetirizine for skin lesion prevention in a canine model of acute atopic dermatitis. Six atopic Maltese‐beagle dogs experimentally sensitized to Dermatophagoides farinae (Df) house dust mites were selected for this study. Twenty‐four hours after challenge by epicutaneous application of Df, erythematous skin lesions were scored. In this blinded, placebo and active controlled study, topical JNJ7777120 or JNJ28307474 was applied as a 1% solution before allergen challenge. The latter was also given orally at 15 mg/kg before and after allergen challenge. A 0.015% triamcinolone acetonide solution was used as a positive control. The H1R antagonists hydroxyzine and cetirizine were administered orally before challenge in a second experiment. Twenty‐four hours after challenge, placebo‐treated animals had a median lesional score of 2. Treatment with topical and oral JNJ28307474 resulted in a median score of 2.5. After topical administration of JNJ7777120, the median lesional score was 2. Hydroxyzine and cetirizine did also not reduce the median score of the placebo treatment. Triamcinolone acetonide prevented all dogs from having any lesions. Determination of histamine in lesions revealed that only during the initiation increased concentrations of histamine were detected. In conclusion, the preventive administration of H1R or H4R antagonists has no impact on the development of acute skin lesions in this experimental canine atopic dermatitis model.