Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept (7.5mg weekly i.v. x12 weeks) was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria. Microarray data from PBMCs of 16 of these patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via nearest shrunken centroid method''. A disease response classifier using 23 genes was created to accurately predict response to alefacept (12.3% error rate in favour of responders). This preliminary study may provide a useful tool to predict response of psoriatic patients with alefacept.
Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept.
Sex, Age, Specimen part, Subject
View SamplesThe success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal migr-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system.
Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.
Subject, Time
View SamplesMild vs. severe psoriasis vulgaris is often distinguished by the Psoriasis Area and Severity Index. It is widely assumed that severe psoriasis involves higher levels of skin inflammation, but comparative molecular profiles of mild vs. severe disease have not been previously performed. In this study, we used gene arrays to phenotype North American patients with mild psoriasis vs. severe psoriasis.
The Spectrum of Mild to Severe Psoriasis Vulgaris Is Defined by a Common Activation of IL-17 Pathway Genes, but with Key Differences in Immune Regulatory Genes.
Disease, Disease stage
View SamplesIn this study, we sought to determine how IL-17 and TNF influence normal human melanocytes, either alone, or with both cytokines together. We reveal a dichotomous effect of IL-17 and TNF, which not only elicit essential mitogenic cytokines but also suppress melanogenesis by down-regulating genes of melanogenesis pathway
IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis.
Specimen part, Treatment, Time
View SamplesPsoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN- is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN--producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN- was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN- indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN- was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN- induced molecular and histological features characteristic of psoriasis lesions. IFN- increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN--treated skin. Thus, IFN-, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis.
A single intradermal injection of IFN-γ induces an inflammatory state in both non-lesional psoriatic and healthy skin.
Disease, Disease stage
View SamplesTo understand the mechanism of disease progression in psoriasis, we defined Asian small plaque psoriasis (small psoriasis) and Asian intermediate plaque psoriasis (intermediate psoriasis) as psoriasis subtypes with limited disease progression, and compared their cellular and molecular signatures with the classic subtype of Western large plaque psoriasis (large psoriasis; GSE30999).
Molecular Phenotyping Small (Asian) versus Large (Western) Plaque Psoriasis Shows Common Activation of IL-17 Pathway Genes but Different Regulatory Gene Sets.
Specimen part, Disease, Disease stage, Treatment, Subject
View SamplesBackground: Previous work has identified CD11c+CD1c- dendritic cells (DCs) as the major inflammatory dermal DC population in psoriasis vulgaris and CD1c+ DCs as the resident cutaneous DC population. Objective: To further define molecular differences between these two myeloid dermal DC populations. Methods: Inflammatory and resident DCs were single-cell sorted from psoriasis lesional skin biopsies, and gene array expression profiling was performed. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double label immunofluorescence. Pooled human keratinocytes were cultured for functional studies. Results: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors (TLRs) 1 and 2, S100A12/EN-RAGE, CD32, and many other inflammatory products were selectively expressed in inflammatory DCs than in resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c- versus CD1c+ DCs. TRAIL receptor, death receptor 4 (DR4), was expressed on basal keratinocytes and blood vessels, and in vitro culture of keratinocytes with rh-TRAIL induced CCL20 leukocyte chemokine. Conclusion: CD11c+CD1c- inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared to skin resident CD1c+ DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.
Identification of TNF-related apoptosis-inducing ligand and other molecules that distinguish inflammatory from resident dendritic cells in patients with psoriasis.
Subject
View SamplesThe process for making monocyte derived DCs (moDCs) has been previously described (46). All analysis was performed on day 5 immature DCs. Etanercept 10mg/mL was added to experimental wells on days 0, 2, and 4. We chose this concentration of etanercept as it approximates the plasma concentration of drug when given 50mg BIW.
Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
No sample metadata fields
View SamplesWe sought to define the cutaneous response at 24 hours following erythemogenic doses of narrow-band UVB (NB-UVB, 312 nm peak) exposure and determine the differences between irradiated and non-irradiated skin.
Gene profiling of narrowband UVB-induced skin injury defines cellular and molecular innate immune responses.
Subject
View SamplesOur group recently described a population of antigen presenting cells that appear to be critical in psoriasis pathogenesis, termed inflammatory myeloid dendritic cells (CD11c+ BDCA1-). Triggering receptor expressed on myeloid cells type-1 (TREM-1) signaling was a major canonical pathway in the published transcriptome of these cells. TREM-1 is a member of the immunoglobulin superfamily, active through the DAP12 signaling pathway, with an unknown ligand. Activation through TREM-1 induces inflammatory cytokines including IL-8, MCP/CCL2 and TNF. We now show that TREM-1 was expressed in the skin of healthy and psoriatic patients, and there was increased soluble TREM-1 in the circulation of psoriasis patients. In psoriasis lesions, TREM-1 was co-localized with dendritic cells as well as CD31+ endothelial cells. TREM-1 expression was reduced with successful NB-UVB, etanercept and anti-IL-17 treatments. An in vitro model of PGN-activated monocytes as inflammatory myeloid DCs was developed to study TREM-1 blockade, and treatment with a TREM-1 blocking chimera decreased allogeneic Th17 activation, as well as IL-17 production. Furthermore, TREM-1 blockade of ex vivo psoriatic dendritic cells in an alloMLR also showed a decrease in IL-17. Together, these data suggest that the TREM-1 signaling pathway offers a novel therapeutic target to prevent the effects of inflammatory myeloid DCs in psoriasis.
TREM-1 as a potential therapeutic target in psoriasis.
Specimen part
View Samples