Effects of <scp>TNF</scp>‐Alpha Inhibitors on Circulating <scp>T</scp>h17 Cells in Patients Affected by Severe Psoriasis

Piaserico, Stefano; Sandini, Elena; Saldan, Alda; Abate, Davide

doi:10.1002/ddr.21202

Cited by 14 publications

(5 citation statements)

References 11 publications

(15 reference statements)

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“…[49] Furthermore, chemokines that are suggested to regulate the Th17 cell population were downregulated ( CXCL1 [50, 51] and IL17A [52]). This supports earlier studies showing that TNF-α inhibition in psoriasis is associated with a substantial Th17 cell-count reduction in the patients’ peripheral blood and that this decrease is significantly associated with an adequate response to biologic therapy [53]. …”

Section: Discussionsupporting

confidence: 91%

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

et al. 2016

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Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.

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Section: Discussionsupporting

confidence: 91%

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

et al. 2016

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“…Our data indicating that anti-TNF may exert its therapeutic effects in HS in part by reducing the extremely high expression of IL-17 in the skin is to our knowledge previously unreported. Similar findings have been observed in psoriasis patients treated with anti-TNF (Piaserico et al, 2014). It would be of interest to determine the benefit of therapeutic targeting of IL-17, or upstream targets such as the inflammasome or IL-23p19, relative to anti-TNF to help to restore T-cell regulation in HS.…”

Section: Discussionsupporting

confidence: 67%

Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy

Moran

Sweeney

Hughes

et al. 2017

Journal of Investigative Dermatology

166

141

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Hidradenitis suppurativa (HS) is a chronic, inflammatory, and debilitating disease of hair follicles with 1-4% prevalence and high morbidity. There is a dearth of information on the pathogenesis and immune dysregulation underlying HS; therefore, we carried out a detailed analysis of skin-infiltrating T cells. Cells isolated from skin biopsy samples and blood from HS patients and healthy control subjects were analyzed by 16-parameter flow cytometry to provide detailed profiles of CD4 T-cell subsets. We observed substantial infiltration of inflammatory T cells with a striking T helper (Th) type 17-skewed cytokine profile in HS skin; these cells expressed the Th17 lineage marker CD161 and IL-17, as well as proinflammatory cytokines GM-CSF, IL-22, IFN-γ, and tumor necrosis factor. Regulatory T cells were also enriched in HS lesional skin; however, the ratio of Th17 to regulatory T cells was nonetheless highly dysregulated in favor of Th17 cells. In contrast, lesional skin from anti-tumor necrosis factor-treated HS patients who showed substantial clinical improvement exhibited a significant reduction in the frequency of Th17 cells and normalization of the Th17 to regulatory T cell ratio. These data suggest that inhibition of pathogenic IL-17 via tumor necrosis factor blockade is associated with improvement in immune dysregulation in HS and may provide a rationale for targeting IL-17 in the disease.

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“…TNF-␣ produced by kidney cells and infiltrating macrophages instigates tubular injury (37,40), so the protective effect of T cell-derived TNF-␣ in our model is surprising and led us to examine renal accumulation of T cell subsets relevant to NTN pathogenesis. The Th17 CD4 subset and Th17-specific cytokines play unique roles in the pathogenesis of kidney disease, and previous studies have reported that TNF-␣ promotes Th17 subset differentiation and Th17 responses in nonrenal tissues (26,31,43). However, we found that both IL-17A mRNA levels and numbers of CD4 ϩ IL-17A ϩ T cells were significantly increased in kidneys from TNF TKO mice.…”

Section: Discussioncontrasting

confidence: 56%

TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis

Wen

Rudemiller

Zhang

et al. 2020

American Journal of Physiology-Renal Physiology

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Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.

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Effects of TNF‐Alpha Inhibitors on Circulating Th17 Cells in Patients Affected by Severe Psoriasis

Cited by 14 publications

References 11 publications

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α

Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy

TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis

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