Development and characterization of a human Th17-driven ex vivo skin inflammation model.

Skin models mimicking features of psoriasis-related inflammation are needed to support the development of new drugs in dermatology. Reconstructed skin models lack tissue complexity, including a fully competent skin barrier, and presence and/or diversity of immune cells. Here, we describe InflammaSkin®, a novel human Th17-driven ex vivo skin inflammation model. In this model, skin-resident T cells are in situ activated by intradermal injection of anti-CD3 and anti-CD28 antibodies and Th17 cell polarization is sustained by culture in a chemically defined medium supplemented with IL-1ß, IL-23 and TGF-ß for seven days. The acquired Th17 signature is demonstrated by the sustained secretion of IL-17A, IL-17AF, IL-17F, IL-22, IFN-γ, and to some degree IL-15 and TNF-α observed in the activated ex vivo skin inflammation model compared with the non-activated skin model control. Furthermore, expression of S100A7 and Keratin-16 by keratinocytes and loss of epidermal structure integrity occur subsequently to in situ Th17cell activation, demonstrating cellular crosstalk between Th17 cells and keratinocytes. Finally, we demonstrate the use of this model to investigate the modulation of the IL-23/IL-17 immune axis by topically applied anti-inflammatory compounds. Taken together, we show that by in situ activation of skin-resident Th17 cells, the InflammaSkin® model reproduces aspects of inflammatory responses observed in psoriatic lesions and could be used as a translational tool to assess efficacy of test compounds.

Small-Group, Community-Member Intervention for Urinary and Bowel Incontinence: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of Mind Over Matter: Healthy Bowels, Healthy Bladder, a small-group intervention, on urinary and bowel incontinence symptoms among older women with incontinence. METHODS: In this individually randomized group treatment trial, women aged 50 years and older with urinary, bowel incontinence, or both, were randomly allocated at baseline to participate in Mind Over Matter: Healthy Bowels, Healthy Bladder immediately (treatment group) or after final data collection (waitlist control group). The primary outcome was urinary incontinence (UI) improvement on the Patient Global Impression of Improvement at 4 months. Validated instruments assessed incontinence, self-efficacy, depression, and barriers to care-seeking. Intent-to-treat analyses compared differences between groups. Target sample size, based on an anticipated improvement rate of 45% in treated women vs 11% in the control group, 90% power, type I error of 0.05, with anticipated attrition of 25%, was 110. RESULTS: Among 121 women randomized (62 treatment group; 59 control group), 116 (95%) completed the 4-month assessment. Most participants were non-Hispanic white (97%), with a mean age of 75 years (SD 9.2, range 51-98); 66% had attended some college. There were no significant between-group differences at baseline. At 4 months, 71% of treated women vs 23% of women in the control group reported improved UI on Patient Global Impression of Improvement (P<.001); 39% vs 5% were much improved (P<.001). Regarding bowel incontinence, 55% of treated women vs 27% of women in the control group improved on Patient Global Impression of Improvement (P<.005), with 35% vs 11% reporting much improvement (P<.005). Treated women improved significantly more than women in the control group on all validated instruments of incontinence severity, quality of life, and self-efficacy. Care-seeking rates were similar between groups. CONCLUSION: Participation in a small-group intervention improves symptoms of both urinary and bowel incontinence in older women. Mind Over Matter is a feasible model with potential to bring effective behavioral solutions to the community. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03140852.