Inhibition of the IL-2-inducible tyrosine kinase (Itk) activity: a new concept for the therapy of inflammatory skin diseases.

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.

Grants4Targets - an innovative approach to translate ideas from basic research into novel drugs.

Collaborations between industry and academia are steadily gaining importance. To combine expertises Bayer Healthcare has set up a novel open innovation approach called Grants4Targets. Ideas on novel drug targets can easily be submitted to http://www.grants4targets.com. After a review process, grants are provided to perform focused experiments to further validate the proposed targets. In addition to financial support specific know-how on target validation and drug discovery is provided. Experienced scientists are nominated as project partners and, depending on the project, tools or specific models are provided. Around 280 applications have been received and 41 projects granted. According to our experience, this type of bridging fund combined with joint efforts provides a valuable tool to foster drug discovery collaborations.

Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs.

Beyond its effects on bone metabolism, calcium and phosphorus homeostasis, 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3), calcitriol) exerts profound effects on the immune system. We here provide an overview over the metabolism, molecular and cellular action of 1,25(OH)(2)D(3) with particular regard to its immunomodulatory function. Effects of 1,25(OH)(2)D(3) on the immune system are manyfold and include suppression of T cell activation, shaping of cytokine secretion patterns, induction of regulatory T cells, modulation of proliferation, and interference with apoptosis. 1,25(OH)(2)D(3) further influences maturation, differentiation, and migration of antigen presenting cells. Altogether, its immunomodulatory potency is comparable to other established immunosuppressants without sharing their typical adverse effects. This profile makes 1,25(OH)(2)D(3) a potential drug for the treatment of immune-mediated diseases. Yet, the major obstacle for its clinical use, its potent calcemic activity, is not overcome to date. The identification or generation of novel vitamin D derivatives with dissociated calcemic and immunomodulatory properties is therefore a major task. Its success might eventually lead to promising drugs for future therapeutic exploitation of a wide array of immune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and others.

An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile.

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.