scholarly journals LOCAL AND SYSTEMIC IMMUNE PARAMETERS IN SEVERE ATOPIC DERMATITIS AND CUTANEOUS T-CELL LYMPHOMA PATIENTS

2013 ◽  
Vol 10 (5) ◽  
pp. 13-21
Author(s):  
D D Niyazov ◽  
E S Fedenko ◽  
M N Boldyreva ◽  
D Yu Trofimov
Keyword(s):  
Gene Expression ◽  
Atopic Dermatitis ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Lymphoma ◽  
Severe Atopic Dermatitis ◽  
Cutaneous T Cell Lymphoma ◽  
Healthy Donors ◽  
Genes Expression ◽  
Skin Samples

Background.. To investigate expression of cytokines genes parameters in skin and blood in severe atopic dermatitis (AD) and cutaneous T-cell lymphoma (CTCL) patients comparing with healthy donors. Materials and methods. 20 severe AD patients, 20 CTCL patients and 20 healthy donors were included in the study. Skin samples and peripheral blood were used as material for immunological study. Interleukins — (IL)1B, IL2, IL2r, IL4, IL5, IL6, IL7, IL8, IL10, IL12A, IL12B, IL15 (total), IL15 , IL17A, IL18, IL23, IL28, IL29, Interferon γ (IFNγ), tumor necrosis factor α (TNFα), transforming growth factor beta 1 (TGFB1), forkhead box P3 (FOXP3) gene expression was defined in the skin and peripheral blood of severe AD patients, CTCL patients and healthy donors by real-time reverse transcription polymerase chain reaction (RT-PCR). Results. Statistically significant increase of cytokines genes IL4,IL12B,IL17A, TNFα in peripheral blood of severe AD patients compared with CTCL patients was marked. Studying of skin samples from CTCL patients has shown statistically significant increase of cytokines IL8, IL10, IL15, IFNγ genes expression and decrease of IL18 gene expression in comparison with skin samples from severe AD patients. Conclusion. Obtained cytokines genes expression cytokines genes parameters in peripheral blood of severe AD and CTCL patients had a certain similarities consisting of increased IL8, IFNγ and decreased IL6, IL23 genes expression in comparison with healthy donors. Substantial differences in peripheral blood of patients in comparison with healthy donors: increased IL-5, IL-12B genes expression in AD patients and decreased IL-8, IL-12A genes expression in CTCL patients, at the same time increased expression of IL-6, IL-8, IL-10, IFNγ genes in severe AD and CTCL patients were shown.

Cutaneous T Cell Lymphoma Complicating Severe Atopic Dermatitis

Dermatology ◽  
2008 ◽  
Vol 218 (2) ◽  
pp. 168-171 ◽  
Author(s):  
Nicolas Meyer ◽  
Juliette Mazereeuw-Hautier ◽  
François Launay ◽  
Laurence Lamant ◽  
Carle Paul
Keyword(s):  
Atopic Dermatitis ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Severe Atopic Dermatitis ◽  
Cutaneous T Cell Lymphoma

scholarly journals Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma and Atopic Dermatitis

2017 ◽  
Vol 97 (10) ◽  
pp. 1172-1177 ◽  
Author(s):  
T Oka ◽  
M Sugaya ◽  
N Takahashi ◽  
R Nakajima ◽  
S Otobe ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

Identification of Informative Gene Expression Signatures Indicative of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Exposure and Clinical Efficacy in Patients with Advanced Cutaneous T-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4686-4686 ◽  
Author(s):  
Andrey Loboda ◽  
Valeria Fantin ◽  
Sophia Randolph ◽  
Justin L. Ricker ◽  
James S. Hardwick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoid Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Gene Expression Signatures ◽  
Lymphoid Cell Lines

Abstract Vorinostat is a histone deacetylase inhibitor currently under evaluation in numerous oncology clinical trials. In a Phase IIb trial, oral vorinostat resulted in a 29.7% overall objective response rate in patients (pts) with advanced cutaneous T-cell lymphoma (CTCL) and had an acceptable safety profile. These results prompted efforts to identify gene expression patterns that could elucidate the molecular mechanism of action (MOA), assess exposure to vorinostat and enrich for pts who are likely to respond. In the Phase IIb trial, gene expression profiles were obtained from 24 predose and 30 postdose (2 hr postdose on Day 15) PBMC samples. The gene expression associated with Sezary burden was easily identified in predose samples and consistent with published results. Although the power of this dataset was limited for development of a predose predictor of response, we identified three biologically-relevant pathways that correlated with response and deserve further validation. First, we found a coherent cluster of proliferation/cell cycle genes to be associated with resistance to therapy. This may imply that tumor aggressiveness is an important factor for clinical response. Second, a set of antioxidant genes was upregulated in non-responders. The generation of reactive oxygen species (ROS) is a component of the vorinostat MOA and increased ROS scavenging ability may confer resistance. Finally, cytotoxic cell markers were upregulated in responders and may represent another factor associated with contribution of T and NK cells to response. Each of these 3 patterns, if confirmed, would allow for 20–50% responder enrichment. We observed robust postdose gene expression changes in which ~942 genes exhibited significant regulation (fold-change>2, P<0.01 by paired t-test between predose and postdose samples) regardless of clinical outcome. Treated samples were discriminated from untreated with 87.5% accuracy based on leave one-out-cross-validation (LOOCV) using penalized analysis of microarrays (PAM). To understand the biology, we projected the preclinical postdose signatures derived from acute postdose changes in a panel of human lymphoid cell lines. Overall, 85% of genes significantly regulated by vorinostat in lymphoid cell lines were also regulated in the same direction in PBMC samples from CTCL pts. Thus, most of the observed postdose changes result from acute vorinostat effects on gene expression. The average preclinical postdose signature can be used to predict proximal vorinostat exposure with 90% accuracy. Among the gene expression signatures observed in clinical samples but not in cell lines, two deserve special attention. First, proliferation-associated genes are downregulated postdose and are differentially expressed between responders and non-responders. It may serve as an efficacy biomarker and would allow for 80% accurate discrimination of responders from non-responders in postdose samples based on LOOCV using PAM. Second, cytokines and genes associated with the humoral immune response were downregulated at the same time genes and cytokines associated with a cytotoxic immune response were upregulated. Such changes in the Th1-Th2 balance may reflect part of the MOA for vorinostat, and may be particularly relevant to CTCL, a disease caused by Th2 type skin-homing lymphocytes. Further evaluation of vorinostat in CTCL, including additional validation of gene expression signatures that may predict response, is warranted.

Biomarkers of Vorinostat Resistance in Cutaneous T-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1381-1381
Author(s):  
Chunlei Zhang ◽  
Baoqiang Li ◽  
Rakhshandra Talpur ◽  
C. Cameron Yin ◽  
Madeleine Duvic
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Mononuclear Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Cutaneous T Cell Lymphoma ◽  
Phase Ii Studies

Abstract Profiling gene expression with DNA microarray technology has elucidated novel therapeutic targets and led the approval of a number of targeted therapeutic agents for the treatment of cancer. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a pan-histone deacetylase (HDAC) inhibitor that has demonstrated an overall response rate of approximately 24–30% in two phase II studies of cutaneous T cell lymphoma (CTCL) patients. There are currently no known specific biomarkers to indicate resistance to vorinostat. To identify genes resistant to vorinostat we compared profiles using the Aligent whole human genome oligo microarrays containing ∼41,000 genes/transcripts in vitro in vorinostat-resistant MJ and -sensitive HH CTCL cell lines treated with 1 μM of vorinostat for 24 hours and compared them to patients’ peripheral blood mononuclear cells (PBMCs) before and during oral therapy. There were 3151 (7.7%) genes/transcripts differentially expressed in vitro in treated resistant MJ cells compared to untreated vehicle control (p < 0.001). We also studied differential gene expression in two clinically resistant Sézary patients’ PBMCs taken at baseline and four weeks after oral vorinostat (400 mg daily or 300 mg bid 3 days/wk). In patients’ PBMCs, 585 (1.4%) and 2744 (6.7%) differentially expressed genes/transcripts (p < 0.001) were identified, respectively. Genes that were up-regulated both in vitro and in vivo included a tumor necrosis factor receptor super-family member 11a (TNFRSF11a or RANK), matrix metallopeptidase 9 (MMP9), suppressor of cytokine signaling 3 (SOCS3), vinculin (VCL) and KIAA1840. Genes that were down-regulated in both included adenylate kinase 3-like 1 (AK3L1), leucine rich repeat and fibronectin type III domain containing 4 (LRFN4), and AL359650. Increased RANK, MMP9 and SOCS3 mRNA expression in MJ compared to HH cells and in three resistant versus three vorinostat responding Sézary patients’ PBMCs was confirmed using quantitative real-time PCR. In conclusion, our results suggest that oligonucleotide microarray analysis may identify biomarkers of resistance to vorinostat which would be helpful to select patients who may not benefit from treatment. These findings provide the rationale for future functional studies and development of more effective use of HDAC inhibitors for CTCL patients.

scholarly journals Dysregulated Synthesis of Intracellular Type 1 and Type 2 Cytokines by T Cells of Patients with Cutaneous T-Cell Lymphoma

1999 ◽  
Vol 6 (1) ◽  
pp. 79-84 ◽  
Author(s):  
Bang-Ning Lee ◽  
Madeleine Duvic ◽  
Chih-Kwang Tang ◽  
Carlos Bueso-Ramos ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
Study Groups ◽  
Cutaneous T Cell Lymphoma ◽  
Healthy Donors ◽  
Type 2 Cytokines ◽  
Ifn Γ

ABSTRACT Mycosis fungoides (MF) and Sezary syndrome (SS) are the two main clinical entities of cutaneous T-cell lymphoma (CTCL). As the disease progresses from MF to SS, a switch from a type 1 (interleukin [IL]-2 and gamma interferon [IFN-γ]) to a type 2 (IL-4) cytokine production profile occurs. Although roles for type 1 and type 2 cytokines in the pathogenesis of CTCL have been proposed, the cellular origins of these cytokines are unclear. Using flow cytometry to identify individual T-cell subsets, we studied cytokine synthesis by the T cells of 13 patients with SS and 12 with MF and 9 hematologically healthy donors. Upon activation with phorbol 12-myristate 13-acetate (PMA), the numbers of T cells synthesizing IL-2 were similar for all study groups. Whereas the predominant T-cell producing IL-2 in healthy donors and in those with MF was CD7+, in patients with SS, it was CD7−. Although the number of IL-4+CD4+ T cells was low for all study groups, there was a significantly higher number of IL-4+ CD8+ T cells in patients with MF than in those with SS or healthy donors. There was a decline in the number of IFN-γ-producing T cells in CTCL donors compared to that in healthy donors. More importantly, there was a significant decrease in the number of IFN-γ-producing T cells with disease progression from MF to SS. The inability of these T cells to synthesize IFN-γ may have prognostic value in CTCL, since it may be responsible for the progression of the disease from MF to SS.

scholarly journals Cutaneous T-cell Lymphoma and Concomitant Atopic Dermatitis Responding to Dupilumab

2020 ◽  
Vol 106 (3) ◽  
Author(s):  
Nicholas K Mollanazar ◽  
Kevin T Savage ◽  
Bobak T Pousti ◽  
Neha Jariwala ◽  
Christina Del Guzzo ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

Isolation of Tumor-Specific Cytotoxic CD4+ and CD4+CD8dim+ T-Cell Clones Infiltrating a Cutaneous T-Cell Lymphoma

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4331-4341 ◽  
Author(s):  
Martine Bagot ◽  
Hamid Echchakir ◽  
Fathia Mami-Chouaib ◽  
Marie-Hélène Delfau-Larue ◽  
Dominique Charue ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Autologous Tumor ◽  
Cutaneous T Cell Lymphoma ◽  
T Cell Clones ◽  
Cell Clones

We have isolated several T-cell clones from lymphocytes infiltrating a human major histocompatibility class (MHC) II negative cutaneous T-cell lymphoma (CTCL). We describe here two of these clones, TC5 and TC7, with, respectively, a CD4+CD8dim+ and CD4+CD8− phenotype. Both clones mediated a specific MHC class I–restricted cytotoxic activity toward the fresh autologous tumor cells, and autologous tumor cell lines previously established with interleukin-2 (IL-2) and IL-7 from the skin and from the blood. Analysis of the T-cell receptor (TCR) Vβ gene expression showed that the tumor cells, which were shown to have a trisomy 7 by fluorescent in situ hybridization, expressed Vβ7/Jβ2.3, Vβ13/Jβ2.5, and Vβ22/Jβ2.5 rearrangements. Phenotypic analysis using specific anti-Vβ monoclonal antibodies indicated that only Vβ13 could be detected on the cell membrane of the tumor cells. Analysis of the TCR Vβ gene expression of the clones showed that TC5 and TC7 expressed a unique TCR-Vβ transcript, corresponding, respectively, to Vβ5/Jβ2.3 and Vβ17/Jβ2.7 gene segments. To determine whether these reactive T lymphocytes were present in vivo, we used specific primers corresponding to TC5- and TC7-Vβ TCR transcripts. The results showed that both cytotoxic T-cell clones were present at the lesional skin site and amplified in vitro. TC7 was found in the patient peripheral blood invaded by tumoral cells, whereas TC5 was not, indicating that the repertoire of the reactional lymphocytes differs in the blood and at the tumor site. These results show for the first time the presence of reactive T lymphocytes with CD4 or double-positive phenotype infiltrating a CTCL. These findings raise the question of the role of these antitumoral effector T cells in the tumor growth.

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