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Heme oxygenase-1 (HO-1) is increased in psoriatic skin. We asked for the impact of physiological and pharmacological HO-1 induction on skin immunity and the mechanisms involved in HO-1-induced immunomodulation. We found cutaneous HO-1 expression upregulated comparable with suppressors of cytokine signalling (SOCS)1 and SOCS3 in psoriasis and atopic eczema and temporarily increased in murine ovalbumin-induced late phase reaction (LPR) and 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). Cutaneous inflammation was enhanced by HO-1 inhibition and was abrogated by treatment with the HO-1 inducer cobaltic protoporphyrin (CoPP) both when applied around sensitization or before challenge. HO-1 inhibition specifically prevented the anti-inflammatory CoPP effect. CoPP inhibited T cell proliferation in splenocytes of treated mice and in human mixed leukocyte reaction and lymphocyte transformation test. CoPP induced HO-1 in antigen-presenting cells and depressed monocytic accessory molecule expression and the differentiation and maturation of monocyte-derived dendritic cells (MDDC). It decreased tumor necrosis factor (TNF)-α and interleukin (IL)-12 production while increasing IL-10 secretion. The antigen-presenting capacity was diminished in CoPP-treated and HO-1-transduced MDDC. We demonstrate for the first time the physiological role of HO-1 in the limitation of skin inflammation and implement pharmacological HO-1 induction as a therapeutic approach for T cell-dependent inflammatory dermatoses. Suppression of antigen-presenting cells may represent a main anti-inflammatory mechanism of HO-1. [ABSTRACT FROM AUTHOR]

Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl LewisX mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future. [ABSTRACT FROM AUTHOR]

T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high-throughput screening hit, inhibited Itk's activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR-induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T-cell-mediated inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Psoriasis, atopic dermatitis and allergic contact dermatitis are T-cell-mediated inflammatory skin diseases; chemokine receptors (CCR) 4 and 10 play an important role in the ligand-mediated recruitment of T cells into the skin in mice and humans, specifically with regards to tethering, firm adhesion and subsequent extravasation to the sight of injury. We utilized established murine models of dinitrofluorobenzene-, trimellitic acid anhydride- or oxazalone-induced contact hypersensitivity, to reflect the various Th-polarizations of different skin diseases, and investigated the functional effect of antibody blocking of single CCR ligands or combination therapy to block all CCR4 and CCR10 ligands. Our results indicate a greater reduction in inflammatory response – measured by oedema formation, myeloid cell and neutrophil infiltration and activity and CD3+ cell infiltration at the site of injury – with combination antibody therapy to CCR4 and CCR10 ligands versus controls, in nearly every tested condition. We conclude that blocking CCR4 and CCR10 simultaneously, or their ligands, should be beneficial in the treatment of T-cell-mediated skin diseases. [ABSTRACT FROM AUTHOR]

Background: T cells play a central role in many inflammatory diseases, hence the identification and validation of T cell-specific target genes will increase the understanding of T cell function in pathologic inflammatory situations. RNA interference (RNAi), with its ability to induce specific gene silencing in mammalian cells, represents a powerful technology to investigate and validate the function of pharmaceutical target genes in vitro and in vivo. The aim of the present study was to systematically explore RNAi-mediated gene-silencing of known T cell-specific model signaling molecules in primary murine T cells in vitro and in vivo. Results: We demonstrate that siRNA delivery and subsequent silencing of T cell specific genes is substantially increased, if murine T cells were activated prior siRNA transfection. Silencing of ZAP70, p56Lck as well as PLC-γ1 protein expression resulted in impaired function of T cells in vitro. Furthermore, delayed type hypersensitivity (DTH) was ameliorated in vivo after adoptive transfer of ZAP70-silenced T cells. Coclusion: The combination of RNAi-mediated gene silencing and adoptive transfer of gene-silenced T cells, thus, may allow the identification and analysis of T cell-specific targets for therapeutic intervention. Additionally, this model system may represent an alternative to conventional time consuming and cost intensive gene targeting approaches. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin disease that affects about 1.5% of the Caucasian population and is characterized by typical macroscopic and microscopic skin alterations. Psoriatic lesions are sharply demarcated, red and slightly raised lesions with silver-whitish scales. The microscopic alterations of psoriatic plaques include an infiltration of immune cells in the dermis and epidermis, a dilatation and an increase in the number of blood vessels in the upper dermis, and a massively thickened epidermis with atypical keratinocyte differentiation. It is considered a fact that the immune system plays an important role in the pathogenesis of psoriasis. Since the early 1990s, it has been assumed that T1 cells play the dominant role in the initiation and maintenance of psoriasis. However, the profound success of anti-tumor necrosis factor-α therapy, when compared with T-cell depletion therapies, should provoke us to critically re-evaluate the current hypothesis for psoriasis pathogenesis. Recently made discoveries regarding other T-cell populations such as Th17 and regulatory T cells, dendritic cells, macrophages, the keratinocyte signal transduction and novel cytokines including interleukin (IL)-22, IL-23 and IL-20, let us postulate that the pathogenesis of psoriasis consists of distinct subsequent stages, in each of them different cell types playing a dominant role. Our model helps to explain the varied effectiveness of the currently tested immune modulating therapies and may enable the prediction of the success of future therapies. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects. [ABSTRACT FROM AUTHOR]

1α,25-Dihydroxyvitamin D3 , the biologically active form of vitamin D3 , is a potent immunomodulatory molecule; however, its clinical use as an immunosuppressant is limited due to its strong effects on calcium homeostasis and the risk of associated side-effects. Here, we present a representative of a novel class of vitamin D analogs that exhibits potent immunosuppressive activity in a murine model of contact hypersensitivity when applied systemically and is efficacious also at nonhypercalcemic dosages. In vitro analysis revealed a binding affinity of ZK 191784 to the vitamin D receptor comparable with 1,25-dihydroxyvitamin D3 . This compound inhibits lymphocyte proliferation and secretion of tumor necrosis factor α and interleukin-12 in monocytes in a concentration-dependent manner, but with reduced potency and efficacy than 1,25-dihydroxy-vitamin D3 . Treatment of human monocytes with this analog significantly reduces expression of major histocompatibility complex class II, B7.1, and intercellular adhesion molecule-1 equipotent to 1,25-dihydroxyvitamin D3 . Interestingly, the compound failed to induce vitamin D-induced differentiation of human promyelocytic leukemia cell line HL-60 to monocytes and was capable of antagonizing the action of 1,25-dihydroxyvitamin D3 . In vivo , as analyzed in mice the compound potently inhibits the contact hypersensitivity when applied systemically. ZK 191784 has a clear therapeutic advantage over 1,25-dihydroxyvitamin D3 by inducing immunosuppressive effects also at concentrations that do not cause hypercalcemia. ZK 191784 is the first representative of a novel class of vitamin D analogs that might have therapeutic potential in T cell-mediated immune disorders. [ABSTRACT FROM AUTHOR]