Abstract Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8+ T cells and natural killer cells. We report phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety tolerability by determining dose-limiting toxicity (DLT). secondary objectives were identify dose response for various biomarkers the peripheral blood, estimate minimum biologically effective dose,...

Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8(+) T cells, natural killer (NK) and other cell types. We report final clinical biological results phase II study recombinant human IL-21 (rIL-21) in patients with metastatic melanoma.Open-label, single-arm, two-stage trial.unresectable melanoma, measurable disease by Response Evaluation Criteria Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance...

Interleukin (IL)-21 is a novel cytokine that has been shown to enhance proliferation and activation of CD8+ T cells, natural killer (NK) cell activity costimulate anti-CD40-driven B-cell in mice. Several studies have furthermore demonstrated antitumour effects IL-21 administration mouse models. In this study we investigated how affects the survival cytotoxicity human NK cells modulates their expression surface receptors effector molecules granzyme B perforin. contrast murine where alone...

Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the effects of systemic IL-21 therapy system two phase 1 trials with this novel cytokine. Recombinant was administered by intravenous bolus injection at dose levels from to 100 μg/kg using planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily five consecutive days followed nine dose-free (5 + 9). The following biomarkers were studied...

Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences gene expression lesional from patients mild extrinsic or intrinsic AD compared healthy controls psoriasis skin. The primary aim was identify differentially expressed genes involved barrier formation inflammation, compare our results those reported for moderate severe AD. contrast AD, of the...

Abstract Squamous cell carcinoma (SCC) is the second most common human skin cancer and leading cause of cancer–related death. Recently, a new compound, ingenol mebutate, was approved for treatment actinic keratosis, precursor SCC. As mechanism action poorly understood, we have further investigated mebutate–induced We elucidate direct effects mebutate on primary keratinocytes, patient-derived SCC cells, line. Transcriptional profiling followed by pathway analysis performed mebutate–treated...

Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared efficacy subcutaneous and intratumoral (IT) administration IL-21 protein two syngeneic mouse tumor models, RenCa renal cell carcinoma B16 melanoma, investigated mechanisms by which enhances CD8 T-cell-mediated antitumor immunity. We found that comparison to administration, IT more potently inhibited growth increased survival. This correlated with densities...

Abstract IL-21, a member of the common γ-chain family cytokines, has pleiotropic effects on T, B, and NK cells. We found that IL-21 prototype cytokine IL-2 can stimulate proliferation secretion by Ag-specific rhesus monkey CD8+ T However, unique among members this we drives these cells to apoptosis down-regulation Bcl-2. These findings suggest may play an important role in contraction cell responses.

There is a lack of efficacious topical treatments for patients suffering from psoriatic nail disease (PND). We investigated the efficacy Calcipotriol-Betamethasone Dipropionate (Cal/BD) foam with and without ablative fractional laser (AFL) in PND. A total 144 nails 11 were treated 24-week long, open-label, randomized, intra-patient controlled proof-of-concept hybrid trial. In addition to daily Cal/BD application, half each patient's randomized receive optical coherence tomography...

Interleukin-21 (IL-21) is a common γ-chain cytokine produced by T helper and natural killer (NKT) cells. It has been shown to regulate the response of various lymphocyte subsets including NK, NKT, B Owing its potent anti-tumor function in preclinical studies ability induce cytotoxicity interferon-γ (IFN-γ) production NK CD8 cells, recombinant IL-21 (rIL-21) was fast-tracked into early-phase clinical trials patients with malignancies. In phase 2a trial metastatic melanoma, we analyzed...

Ingenol mebutate is approved for the topical treatment of actinic keratoses and may ultimately also find utility in treating skin cancers. Here we show that relapse rates subcutaneous B16 melanoma tumours treated topically with ingenol were not significantly different C57BL/6 Rag1-/- mice, suggesting B T cells do play a major role anti-cancer efficacy mebutate. Relapse were, however, increased MyD88-/- mice anti-IL-1 agent, anakinra. induces pronounced infiltration neutrophils, which have...

Treatment with ATP-sensitive K(+) channel openers (KCOs) leads to inhibition of insulin secretion and metabolic "rest" in beta-cells. It is hypothesized that type 1 diabetes this may reduce beta-cell death resulting from stress as well the immunogenicity beta-cells during autoimmune destruction. We have investigated whether beta-cell-selective KCO compound, NN414, can be used improve survival DR-BB rats rendered diabetic by modulation their immune system. The were treated three times daily...

During an autoimmune process, the autoaggressive response spreads from initiating autoantigen to other antigens expressed in target organ. Based on evidence experimental models for multiple sclerosis, such “antigenic spreading” can play important role exacerbation of clinical disease. We evaluated whether pathogenesis spontaneous diabetes NOD mice could be accelerated a similar way when novel was pancreatic β-cells. Unexpectedly, we found that expression lymphocytic choriomeningitis virus...

Abstract IL-21 has antitumor activity through actions on NK cells and CD8+ T cells, is currently in clinical development for the treatment of cancer. However, no studies have addressed role endogenous tumor immunity. In this study, we studied both primary secondary immune responses IL-21−/− IL-21R−/− mice against several experimental tumors. We found intact surveillance toward methylcholanthrene-induced sarcomas compared with wild-type B16 melanomas showed equal growth kinetics lung...

Ingenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and characterized by high sustained clearance lesions. The inherent propensity ingenol towards chemical rearrangement necessitates refrigeration final product. We sought to identify novel derivatives with enhanced stability similar or improved in vitro potency vivo efficacy. A number esters were synthesized full regiocontrol from ingenol. Chemical was determined aqueous buffer at...

Digital pathology and image analysis have developed extensively during the last couple of years. Especially advance in whole-slide scanning, software, computer processing makes it possible to apply these methods tissue-based research. Today this task is dominated by tedious manual assessments pathologists with interobserver intraobserver variation includes. Automated quantitative assessment immunohistochemical staining has potential objectively extract numerical measures from cell tissue...

The initial events leading to activation of the immune system in type 1 diabetes are still largely unknown. In vivo, dendritic cells (DCs) thought be only antigen-presenting (APCs) capable activating naïve T-cells and therefore important for initiation autoimmune response. To test effect islet-associated APCs situ, we generated transgenic mice expressing CD154 (CD40 ligand) under control rat insulin promoter (RIP). RIP-CD154 developed both insulitis diabetes, although with different...