Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.

Histone deacetylase inhibitors are under investigation in the clinic as a new class of anti-cancer therapeutics. While recent studies have also suggested their potential as inhibitors of a wide spectrum of inflammatory reactions, the anti-inflammatory mechanism of action of these compounds is not fully defined. We show here that the histone deacetylase inhibitors MS-275 and SAHA induce the generation of regulatory T cells (Tregs) from anti-CD3/anti-CD28-stimulated human CD4(+)CD25(-) T cells. These Tregs express the regulatory T cell-associated transcription factor Foxp3 and display suppressive activity against CD4(+)CD25(-) T cell proliferation. Topical treatment with histone deacetylase inhibitors also induces Foxp3 expression in the draining lymph nodes and the skin in the context of a murine contact hypersensitivity model. These findings suggest that Treg generation may serve as a novel mechanism by which histone deacetylase inhibitors regulate the immune response, and provide an additional rationale for the use of histone deacetylase inhibitors in the treatment of inflammation.

CCR4 and CCR10 ligands play additive roles in mouse contact hypersensitivity.

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.

Guinea pig maximization test assessment of hydrocortisone and tixocortol pivalate.

The anti-inflammatory properties of topical corticosteroids are well documented; additionally, their sensitization potential is also known. We aimed to assess the relative sensitization potential of hydrocortisone and tixocortol pivalate in an animal assay as it relates to potential for sensitization in humans. Using the guinea pig maximization test (GPMT), animals were sensitized intradermally on d0, and again topically on d7. On d21 the animals were challenged topically with a closed patch for 24 h and readings were taken 24 h and 48 h post-challenge. A sham control group received the same induction and challenge applications excluding the test agent. Animals were subsequently rechallenged with open application; the tixocortol pivalate group was further retested at different test agent concentrations to determine threshold concentration that elicited response. Tixocortol pivalate resulted in sensitization rates of 42% (24 h) and 80% (48 h); hydrocortisone exhibited 0% (24 h) and 5% (48 h). Scores ranged from 0% (sham group) to 2.4 (48 h tixocortol pivalate). Open rechallenge also resulted in greater tixocortol pivalate sensitization rates compared to hydrocortisone, 82% verse 16% at 48 h, respectively. All tested concentrations of tixocortol pivalate induced sensitization, albeit at differing rates dependant on concentration and timepoint. We conclude that the GPMT remains largely for hazard identification, as it was originally designed, and requires further data sets regarding quantitative induction and elicitation for risk assessment of various compounds in clinical implications.

Interferonß-1b Induces the Expression of RGS1 a Negative Regulator of G-Protein Signaling.

We present evidence of a link between interferonß-1b (IFN-ß) and G-protein signaling by demonstrating that IFN-ß can induce the expression of the negative regulator of G-protein signaling 1 (RGS1). RGS1 reduces G-protein activation and immune cell migration by interacting with heterotrimeric G-proteins and enhancing their intrinsic GTPase activity. In this study, IFN-ß treatment resulted in the induction of RGS1 in peripheral blood mononuclear cells (PBMCs), monocytes, T cells, and B cells. Induction of RGS1 by IFN-ß was concentration dependent and observed at both the RNA and protein level. Other members of the RGS family were not induced by IFN-ß, and induction of RGS1 required the activation of the IFN receptor. In addition, RGS1 induction was observed in PBMCs obtained from IFN-ß-treated multiple sclerosis patients suggesting a possible, as yet unexplored, involvement of G-protein regulation in disease treatment. The upregulation of RGS1 by IFN-ß has not been previously reported.

Relationship of patch test positivity in a general versus an eczema population.

Using previously generated data from multicenter studies European Environmental and Contact Dermatitis Research Group (EECDRG) and North American Contact Dermatitis Group (NACDG), we compare patch test positivity of random sample and eczema populations, attempting to ascertain how one might extrapolate frequency from an eczema group to a general population. We included population-based mathematical estimates for patch test reaction in the general population using the Multinational MONItoring of trends and determinants in Cardiovascular disease MONICA and Clinical Epidemiology and Drug-Utilization Research (CE-DUR) systems. Data analysis provides a ratio of eczema population:random sample population for each allergen and an overall ratio of all allergens 5:1 for actual data and 6:1 for population-based estimates (according to the MONICA and CE-DUR systems). If the positivity rate were the same in each population, the ratio would approximate 1. The individual allergen ratios ranged from formaldehyde at 11.6 to parabens at 1.0, with respect to the NACDG. Some differences may be explained by exposure (neomycin) being greater in patients than in random population. Materials of ubiquitous exposure - i.e. fragrance mix and nickel - had ratios closer to 1. Taken together, data obtained in eczema patients may be viewed as part of a complex biology and may eventually be of use in aiding validation of predictive dermatotoxilogic assays and in public health assessments.

Models in acnegenesis.

Cosmetics and ointments utilized for dermatological purposes often bear unintended and sometimes opposing effects of their indicated use. Although there exists various animal and human models of acnegenesis, such as the Mexican hairless dog, the Rhino mouse, and the rabbit ear assay (REA), an elucidative assay that precisely reflects comedogenesis is not yet available. In this review, acnegenic components--i.e., keratinization, androgens, bacteria, sebum and genetics--are examined on an individual basis and correlated to animal models. Current animal models of comedogenesis focus on individual aspects of a multifaceted clinical condition, acne. Presently, the most commonly used assay is the REA, which possesses a hypersensitive response to acnegenic substances compared to human skin; however, this model is unable to accurately depict the acnegenic potential of chemical compounds, and is therefore only valuable for distinguishing absolute negatives. Developing an animal model that is true to the human condition will require further epidemiological evaluation of acne to elucidate the complex condition.

Superior nuclear receptor selectivity and therapeutic index of methylprednisolone aceponate versus mometasone furoate.

Although introduced more than 50 years ago, topical glucocorticoids are still the first line therapy for many inflammatory skin disorders such as atopic eczema, contact dermatitis and many others. Recently, significant improvements have been made to optimize the ratio of desired to unwanted effects. While with early compounds such as triamcinolone, topical side effects such as skin atrophy and telangiectasias can be observed rather frequently, newer drugs such as methylprednisolone aceponate or mometasone furoate have a significantly improved therapeutic index. The present study compared these two modern topical glucocorticoids, which possess the highest therapeutic index currently found, in terms of nuclear receptor selectivity in vitro and induction of the most important local side effects (skin atrophy and telangiectasias) in a relevant rodent model in vivo. We demonstrate that methylprednisolone aceponate displays higher specificity in nuclear receptor binding compared with mometasone furoate. Methylprednisolone aceponate was also markedly superior in terms of minimizing induction of skin atrophy or telangiectasias when compared with mometasone furoate. Based on these observations, methylprednisolone aceponate is expected to have a greater therapeutic index as compared with mometasone furoate, at least in the test systems used here. The degree to which this observation may translate into a clinical setting requires confirmation.