Ultraviolet (UV) irradiation induces photoaging which is characterized by degeneration of extracellular matrix (ECM) and infiltration of inflammatory cells including neutrophils. Neutrophil elastase (NE), a serine proteinase secreted from neutrophils, degenerates ECM strongly. Since the ECM degeneration accelerates wrinkle formation, NE inhibition is expected to improve wrinkles. This study investigated the effect of an NE inhibitor, C 26 H 32 F 3 N 4 NaO 7 (NEI-L1), which is synthesized with four amino acid derivatives, on wrinkles. Although neutrophils are recruited following UV exposure in mouse skin, there are no reports of their infiltration into wrinkle areas in human skin. To clarify neutrophil infiltration and NE expression around wrinkle areas, immunohistochemistry with NE antibody was performed. While there were no signals in sun-protected skin, many NE-positive cells were found around wrinkles in sun-exposed skin, indicating that NE inhibitors would be a target for improving wrinkles also in human skin. NEI-L1 demonstrated a high inhibitory effect against NE; the IC 50 was 2.93 x 10-7 mol/L. Treatment with NEI-L1 also inhibited ECM degradation induced by recombinant NE in the human skin specimen. To investigate whether NEI-L1 improves wrinkles, a double-blind clinical trial was performed with 68 subjects. Placebo and NEI-L1-containing creams were randomly applied to the left or right side of the corner of eyes in the same subject. Visual assessment by dermatologists and three-dimensional analysis demonstrated that the NEI-L1-containing cream significantly reduced wrinkles in 12 weeks of use, suggesting that NEI-L1 is useful for improving wrinkles.
Background: Extracorporeal photopheresis (ECP) is used to treat chronic graft-versus-host disease (cGVHD). Regulatory T Cells (Tregs) are a potential mechanism. We conducted a prospective multicenter clinical trial to assess association of Tregs with skin response to ECP. Methods: 83 patients with cGVHD enrolled; 9 were excluded due to absent follow up and 8 due to absence of skin cGVHD. 6 months of ECP was recommended: twice a week for 4 weeks, twice a week every 2 weeks for 8 weeks and as determined by provider. Response was assessed by 2005 NIH criteria. The frequency of circulating Tregs was quantified within the CD4+ T-lymphocyte population before and after completion of ECP using flow cytometry on peripheral blood (n¼35). Cutaneous lymphocyte-associated antigen (CLA+) skin-homing Tregs were enumerated as % within total Treg population. Continuous variables were compared using Wilcoxon-rank sum (median [IQR]). Results: 66 patients (67% male), with a median age of 50 (34-60) enrolled. % Body surface area (BSA) erythema decreased from baseline to last visit (6.8 [0.9-15.4] v. 1.7 [0.0-7.2] p ¼.01). BSA sclerosis did not change significantly. 55% of patients had a skin response. 29% had sclerosis, 41% erythema and 30% both. In a logistic regression model, % Tregs and CLA+ Tregs at study entry and completion did not differ between skin responders and non-responders. Conclusions: Our study is one of few to investigate Tregs in ECP for cGVHD. Skin homing Tregs were not increased in patients with skin response, suggesting that Tregs are not the mechanism of action. COI: MJ received research funding and this investigator-initiated research was funded by Therakos, a Mallinckrodt Pharmaceuticals company.
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