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1.
Lancet ; 401(10392): 1941-1950, 2023 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-37105210

RESUMO

BACKGROUND: Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS: In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS: From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION: Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING: French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Cutâneo de Células T , Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Estudos Prospectivos , Síndrome de Sézary/terapia , Síndrome de Sézary/etiologia , Pontuação de Propensão , Linfoma Cutâneo de Células T/terapia , Linfoma Cutâneo de Células T/etiologia , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Micose Fungoide/etiologia , Micose Fungoide/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/etiologia
2.
Exp Dermatol ; 33(5): e15098, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38770557

RESUMO

Healing of complex wounds requires dressings that must, at least, not hinder and should ideally promote the activity of key healing cells, in particular fibroblasts. This in vitro study assessed the effects of three wound-dressings (a pure Ca2+ alginate: Algostéril®, a Ca2+ alginate + carboxymethylcellulose: Biatain alginate® and a polyacrylate impregnated with lipido-colloid matrix: UrgoClean®) on dermal fibroblast activity. The results showed the pure calcium alginate to be non-cytotoxic, whereas the other wound-dressings showed moderate to strong cytotoxicity. The two alginates stimulated fibroblast migration and proliferation, whereas the polyacrylate altered migration and had no effect on proliferation. The pure Ca2+ alginate significantly increased the TGF-ß-induced fibroblast activation, which is essential to healing. This activation was confirmed by a significant increase in Vascular endothelial growth factor (VEGF) secretion and a higher collagen production. The other dressings reduced these fibroblast activities. The pure Ca2+ alginate was also able to counteract the inhibitory effect of NK cell supernatants on fibroblast migration. These in vitro results demonstrate that tested wound-dressings are not equivalent for fibroblast activation. Only Algostéril was found to promote all the fibroblast activities tested, which could contribute to its healing efficacy demonstrated in the clinic.


Assuntos
Alginatos , Movimento Celular , Proliferação de Células , Fibroblastos , Fator A de Crescimento do Endotélio Vascular , Cicatrização , Fibroblastos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Humanos , Alginatos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Colágeno/metabolismo , Bandagens , Fator de Crescimento Transformador beta/metabolismo , Carboximetilcelulose Sódica , Células Cultivadas , Células Matadoras Naturais/efeitos dos fármacos , Resinas Acrílicas , Ácidos Hexurônicos , Ácido Glucurônico , Pele
3.
Exp Dermatol ; 32(7): 1096-1107, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37148203

RESUMO

Keloid scars are hypertrophic and proliferating pathological scars extending beyond the initial lesion and without tendency to regression. Usually, keloids are considered and treated as a single entity but clinical observations suggest heterogeneity in keloid morphologies with distinction of superficial/extensive and nodular entities. Within a keloid, heterogeneity could also be detected between superficial and deep dermis or centre and periphery. Focusing on fibroblasts as main actors of keloid formation, we aimed at evaluating intra- and inter-keloid fibroblast heterogeneity by analysing their gene expression and functional capacities (proliferation, migration, traction forces), in order to improve our understanding of keloid pathogenesis. Fibroblasts were obtained from centre, periphery, papillary and reticular dermis from extensive or nodular keloids and were compared to control fibroblasts from healthy skin. Transcriptional profiling of fibroblasts identified a total of 834 differentially expressed genes between nodular and extensive keloids. Quantification of ECM-associated gene expression by RT-qPCR brought evidence that central reticular fibroblasts of nodular keloids are the population which synthesize higher levels of mature collagens, TGFß, HIF1α and αSMA as compared to control skin, suggesting that this central deep region is the nucleus of ECM production with a centrifuge extension in keloids. Although no significant variations were found for basal proliferation, migration of peripheral fibroblasts from extensive keloids was higher than that of central ones and from nodular cells. Moreover, these peripheral fibroblasts from extensive keloids exhibited higher traction forces than central cells, control fibroblasts and nodular ones. Altogether, studying fibroblast features demonstrate keloid heterogeneity, leading to a better understanding of keloid pathophysiology and treatment adaptation.


Assuntos
Queloide , Humanos , Queloide/metabolismo , Pele/metabolismo , Derme/metabolismo , Fibroblastos/metabolismo , Colágeno/metabolismo , Células Cultivadas
4.
Blood ; 135(14): 1101-1110, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32027747

RESUMO

Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor ß and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.


Assuntos
Paraproteinemias/complicações , Paraproteinemias/terapia , Plasmócitos/patologia , Escleromixedema/complicações , Escleromixedema/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Paraproteinemias/genética , Paraproteinemias/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Plasmaferese , Estudos Retrospectivos , Escleromixedema/genética , Escleromixedema/patologia , Pele/metabolismo , Pele/patologia , Transcriptoma
5.
Mediators Inflamm ; 2022: 5344085, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509434

RESUMO

Skin wounds and compromised wound healing are major concerns for the public. Although skin wound healing has been studied for decades, the molecular and cellular mechanisms behind the process are still not completely clear. The systemic responses to trauma involve the body's inflammatory and immunomodulatory cellular and humoral networks. Studies over the years provided essential insights into a complex and dynamic immunity during the cutaneous wound healing process. This review will focus on innate cell populations involved in the initial phase of this orchestrated process, including innate cells from both the skin and the immune system.


Assuntos
Imunidade Inata , Cicatrização , Imunidade Inata/fisiologia , Imunomodulação , Pele , Cicatrização/fisiologia
7.
Acta Derm Venereol ; 100(13): adv00175, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32449783

RESUMO

The prevalence of psychological disorders in patients with common skin diseases was assessed in a large representative sample of the French adult population. General health, as measured by the EQ5D score, was significantly lower if patients reported having rosacea, atopic dermatitis, urticaria, fungal infections, psoriasis or acne. The proportions of participants reporting being extremely anxious or depressed were higher in those who reported having rosacea, atopic dermatitis or contact dermatitis. Difficulties in sexual and conjugal life were frequently reported by people with psoriasis, atopic dermatitis, contact dermatitis, urticaria and, in particular, acne. Sleep disorders were present in 30-50% of those who reported having acne, rosacea, eczema, psoriasis or urticaria. Sleep disorders may be related not only to pruritus, but also to disfiguring skin diseases. Anxiety and depression complications were mainly reported by those with disfiguring diseases. Sexual and conjugal dysfunctions were associated with all dermatoses (with the exception of warts).


Assuntos
Dermatite Atópica , Eczema , Psoríase , Dermatopatias , Urticária , Adulto , Humanos , Psoríase/diagnóstico , Psoríase/epidemiologia , Dermatopatias/diagnóstico , Dermatopatias/epidemiologia
8.
Exp Dermatol ; 28(1): 80-82, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30431182

RESUMO

Normal ageing is associated with an impaired systemic immune response contributing to an increased susceptibility to infectious diseases. The aim of this study was to compare the lymphocyte phenotype in human skin from old and young healthy subjects. Skin samples from donors were used for explant cultures before flow cytometric analysis. Our results depicted a higher proportion of CD4+ and a lower proportion of CD8+ among CD3+ T cells, a decreased proportion of CD45RA+ naive T cells (3.5 ± 1.9% vs 22.9 ± 11.1%, P ≤ 0.007) and an upregulation of the expression of CD39 and PD1 on CD3+ CD4+ T cells (25.1 ± 8.5% vs 12.5 ± 8.5%, P ≤ 0.003, 68.8 ± 11.6% vs 50.0 ± 11.3%, P ≤ 0.01, respectively) in the skin of old subjects. These findings could explain a reduced generation of long-lived memory T cells and an impaired antitumoral response in the skin of the elderly.


Assuntos
Envelhecimento/metabolismo , Apirase/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Pele/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Complexo CD3/metabolismo , Relação CD4-CD8 , Linfócitos T CD8-Positivos/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Pele/citologia , Adulto Jovem
9.
N Engl J Med ; 369(18): 1704-1714, 2013 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-24131138

RESUMO

BACKGROUND: Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. METHODS: We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. RESULTS: Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. CONCLUSIONS: All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Tinha/genética , Adulto , África do Norte , Idoso , Idoso de 80 Anos ou mais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Feminino , Efeito Fundador , Genes Recessivos , Homozigoto , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Tinha/patologia
10.
Respir Res ; 17: 36, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27044262

RESUMO

In human lung fibrotic lesions, fibroblasts were shown to be closely associated with immature dendritic cell (DC) accumulation. The aim of the present pilot study was to characterize the role of pulmonary fibroblasts on DC phenotype and function, using co-culture of lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and from control patients, with a DC cell line MUTZ-3. We observed that co-culture of lung control and IPF fibroblasts with DCs reduced the expression of specific DC markers and down-regulated their T-cell stimulatory activity. This suggests that pulmonary fibroblasts might sustain chronic inflammation in the fibrotic lung by maintaining in situ a pool of immature DCs.


Assuntos
Comunicação Celular/imunologia , Células Dendríticas/citologia , Fibroblastos/citologia , Fibroblastos/imunologia , Pulmão/citologia , Pulmão/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Citocinas/imunologia , Humanos , Técnicas In Vitro , Fenótipo , Projetos Piloto
11.
Exp Dermatol ; 25(2): 113-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26441147

RESUMO

Dermal fibroblasts play a key role in maintaining skin homoeostasis by synthesizing and degrading extracellular matrix components. During ageing, they are subjected to changes, such as the loss of type I collagen expression and an increased synthesis of metalloproteinase I, leading to fragmentation of collagen fibrils with consequent reduction of the mechanical tension and defects of skin wound healing. Most information about fibroblast ageing was obtained from experiments performed on replicative-senescent dermal fibroblasts in vitro. However, the senescence status of fibroblasts isolated from intrinsically aged skins and its consequences on functionality need to be deeper investigated. Herein, we studied age-related phenotypic and functional alteration of fibroblasts from 'young' (<35 years) and 'old' (>50 years) donors. Our results brought evidence of the senescent status of 'old' fibroblasts by senescence associated ß-galactosidase (SA-ßgal) positive staining and p16 expression. A PCR array focusing on senescence highlighted a subset of downregulated genes including cell cycle progression and ECM genes in 'old' fibroblasts as well as a subset of upregulated genes involved in senescence features. In 'old' fibroblasts, we measured a downregulation of proliferative and contractile capacities of migratory potential under PDGF stimulation and activation into myofibroblasts under TGFß. Old fibroblasts were also more sensitive to oxidative stress than 'young' ones. Of interest, downregulation of p16 expression partially reversed the senescent phenotype of 'old' fibroblasts but failed to restore their functional properties. In conclusion, our data brought evidence of phenotypic and functional differences between fibroblasts from young and intrinsically aged skin that may contribute to the alterations observed with ageing.


Assuntos
Derme/citologia , Fibroblastos/citologia , Envelhecimento da Pele , Adulto , Ciclo Celular , Divisão Celular , Células Cultivadas , Senescência Celular , Colágeno/biossíntese , Colágeno/genética , Inibidor p16 de Quinase Dependente de Ciclina , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes p16 , Humanos , Pessoa de Meia-Idade , Miofibroblastos/citologia , Proteínas de Neoplasias/biossíntese , Fenótipo , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Fator de Crescimento Transformador beta/farmacologia , beta-Galactosidase/biossíntese , beta-Galactosidase/genética
12.
Fam Pract ; 33(6): 580-587, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27623689

RESUMO

BACKGROUND: Qualitative research is often used in the field of general medicine. Our objective was to evaluate the quality of published qualitative studies conducted using individual interviews or focus groups centred on patients monitored in general practice. METHODS: We have undertaken a review of the literature in the PubMed and Embase databases of articles up to February 2014. The selection criteria were qualitative studies conducted using individual interviews or focus groups, centred on patients monitored in general practice. The articles chosen were analysed and evaluated using a score established from the Relevance, Appropriateness, Transparency and Soundness (RATS) grid. RESULTS: The average score of the 52 studies chosen was 28 out of 42. The criteria least often present were the description of the patients who chose not to participate in the study, the justification of the end of data collection, the discussion of the influence of the researchers and the discussion of the confidentiality of the data. The criteria most frequently described were an explicit research question, justified and in relation to existing knowledge, the agreement of the ethical committee and the presence of quotations. The number of studies and the score increased from year-to-year. The score was independent of the impact factor of the journal. CONCLUSIONS: Even though the qualitative research was published in reviews with a low impact factor, our results suggest that this research responded to the quality criteria of the RATS grid. The evaluation scored using RATS could be useful for authors or reviewers and for literature reviews.


Assuntos
Pesquisa Biomédica/normas , Medicina de Família e Comunidade , Pesquisa Qualitativa , Projetos de Pesquisa/normas , Grupos Focais , Humanos , Entrevistas como Assunto , Projetos de Pesquisa/tendências
13.
J Am Acad Dermatol ; 72(6): 1003-9.e1, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25981000

RESUMO

BACKGROUND: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. OBJECTIVE: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. METHODS: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. RESULTS: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. LIMITATIONS: Retrospective design and small sample size are limitations. CONCLUSION: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.


Assuntos
Síndrome de Sézary/patologia , Síndrome de Sézary/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Administração Tópica , Corticosteroides/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha , Terapia Combinada , Dermatite Esfoliativa , Feminino , Seguimentos , França , Humanos , Imuno-Histoquímica , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Fotoferese/métodos , Doenças Raras , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Fatores Sexuais
14.
Cytometry A ; 85(10): 869-82, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25044837

RESUMO

CD160 is a GPI-anchored Ig-like receptor identified by the BY55 mAb on human circulating CD56dim+ NK cells and TCRγδ lymphocytes. In addition, while most intestinal T lymphocytes express it, only a minor circulating CD4+ or CD8+ T lymphocyte subset is CD160+. Here we describe a population of CD4+ CD160+ human blood T lymphocytes of circulating cutaneous T cells. These rare T lymphocytes represent 2.1 ± 1.9% of the circulating CD3+ CD4+ T cells, coexpress CD8αα, CD244, and perforin but lack CD28 expression, a phenotype corresponding to effector memory cytotoxic T-lymphocytes. Functional studies further confirmed their cytotoxic potential. These cells lack αEß7 integrin and CCR7 expression but do express skin-addressing molecules CLA, and CCR4. In normal human skin, CD4+ CD160+ cells represent 34.6 ± 14.7% of the CD4+ T lymphocytes extracted by collagenase treatment. These T cells coexpress CLA (81 ± 13.6%), CCR4 (62.3 ± 15.9%), and some CD8αα (19.6 ± 13%) or CCR7 (24.4 ± 11.7%) expression. Cutaneous T-cell lymphoma cells express the natural killer receptor KIR3DL2 (CD158k) used as a tumor marker. Not only we confirmed the expression of this marker in the blood and/or skin of mycosis fungoides patients but we also show for the first time CD158k expression (often associated with CD160) on cutaneous CD4+ T cells from healthy individuals (25.3 ± 15%). Therefore, CD4+ CD160+ T cells expressing CD158k might represent specialized cutaneous lymphocytes devoted to immune surveillance, from which could originate cutaneous T-cell lymphomas such as mycosis fungoides.


Assuntos
Antígenos CD/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Células Matadoras Naturais/metabolismo , Micose Fungoide/metabolismo , Receptores Imunológicos/biossíntese , Receptores KIR2DL2/biossíntese , Neoplasias Cutâneas/metabolismo , Membrana Celular/metabolismo , Feminino , Citometria de Fluxo/métodos , Proteínas Ligadas por GPI/biossíntese , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Micose Fungoide/diagnóstico , Neoplasias Cutâneas/diagnóstico , Subpopulações de Linfócitos T/metabolismo
15.
Blood ; 120(1): 143-54, 2012 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-22627769

RESUMO

A molecular feature of Sézary syndrome (SS) is the abnormal expression of T-plastin by malignant T cells. Herein, we investigated the molecular mechanisms involved in T-plastin synthesis and the functions of this actin-binding protein, with a special interest in chemoresistance and migration. We confirm the specific expression of T-plastin in peripheral blood lymphocytes (PBLs) from SS patients and its total absence in PBLs from patients with mycosis fungoides, inflammatory cutaneous or hematologic diseases, and from healthy volunteers. Only 3 of 4 SS patients did constitutively express T-plastin. To assess whether T-plastin expression was inducible, T-plastin-negative PBLs were stimulated by phorbol 12-myristate 13-acetate and ionomycin. Our results demonstrate that T-plastin synthesis was induced in negative PBLs from SS patients, other studied patients, and healthy volunteers. Both constitutive and calcium-induced T-plastin expression was down-regulated by calcineurin inhibitors and involved nuclear factor of activated T cells transcription pathway. Constitutive T-plastin expression in SS was associated with resistance to etoposide-induced apoptosis and cell migration toward chemokines (TARC/CCL17, IP-10). In conclusion, T-plastin is a marker restricted to malignant lymphocytes from SS patients and plays a role for cell survival and migration. This opens new strategies for the treatment of SS advanced stages.


Assuntos
Linfoma de Células T/fisiopatologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Síndrome de Sézary/fisiopatologia , Neoplasias Cutâneas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/fisiologia , Biomarcadores/metabolismo , Calcineurina/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Células Jurkat , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/metabolismo , Síndrome de Sézary/genética , Síndrome de Sézary/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Ativação Transcricional/fisiologia
16.
JID Innov ; 4(4): 100273, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39045393

RESUMO

Psoriasis is an inflammatory skin disease characterized by epidermal and immune dysfunctions. Although efficient, current topical treatments display adverse effects, including skin atrophy and burning sensation, leading to poor patient adherence. To overcome these downsides, pickering emulsions were formulated in which the calcitriol-containing dispersed phase was stabilized with either cyclosporin A- or tacrolimus-loaded poly(lactic-co-glycolic) acid nanoparticles. This study aimed to investigate their biological effects on lymphocytes and epidermal cells and their effectiveness in an imiquimod-induced psoriasis-like mouse model. Results showed that both emulsions significantly inhibited nuclear factor of activated T cell translocation in T lymphocytes as well as their IL-2 production, cell activation, and proliferation. In keratinocytes, inhibition of nuclear factor of activated T cell translocation decreased the production of IL-8 and TNF-α. Topical application of emulsions over skin biopsies ex vivo showed accumulation of rhodamin B-coupled poly(lactic-co-glycolic) acid nanoparticles throughout the epidermis by immunofluorescence and significantly decreased the antigen-presenting capacity of Langerhans cells in relation to a reduced expression of activation markers CD40, CD86, and HLA-DR. Using an imiquimod-induced psoriasis model in vivo, pickering emulsions significantly alleviated psoriasiform lesions potentially attributed to the decreased cutaneous expression of T-cell markers, proinflammatory cytokines, chemokines, and specific epidermal cell genes. Altogether, pickering emulsion might be a very efficient formulation for treating inflammatory dermatoses.

17.
EMBO J ; 28(11): 1576-88, 2009 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-19387494

RESUMO

The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after caspase cleavage. However, this role has been challenged by recent observations suggesting a contribution of Acinus in apoptotic internucleosomal DNA cleavage. We report here that AAC-11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinus-mediated DNA fragmentation. AAC-11 was able to protect Acinus from caspase-3 cleavage in vivo and in vitro, thus interfering with its biological function. Interestingly, AAC-11 depletion markedly increased cellular sensitivity to anticancer drugs, whereas its expression interfered with drug-induced cell death. AAC-11 possesses a leucine-zipper domain that dictates, upon oligomerization, its interaction with Acinus as well as the antiapoptotic effect of AAC-11 on drug-induced cell death. A cell permeable peptide that mimics the leucine-zipper subdomain of AAC-11, thus preventing its oligomerization, inhibited the AAC-11-Acinus complex formation and potentiated drug-mediated apoptosis in cancer cells. Our results, therefore, show that targeting AAC-11 might be a potent strategy for cancer treatment by sensitization of tumour cells to chemotherapeutic drugs.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Fragmentação do DNA , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Mapeamento de Interação de Proteínas , Apoptose , Inibidores de Caspase , Linhagem Celular , Humanos , Zíper de Leucina , Ligação Proteica
19.
J Immunol ; 186(9): 5173-83, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21441454

RESUMO

Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3-MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.


Assuntos
Antígenos CD/imunologia , Apoptose/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Evasão Tumoral/imunologia , Antígenos CD/metabolismo , Separação Celular , Citometria de Fluxo , Imunofluorescência , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transfecção , Proteína do Gene 3 de Ativação de Linfócitos
20.
Int J Pharm ; 637: 122870, 2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-36948471

RESUMO

Innovative Pickering emulsions co-encapsulating two active pharmaceutical ingredients (API) were formulated for a topical use. An immunosuppressive agent, either cyclosporine A (CysA) or tacrolimus (TAC), was encapsulated at high drug loading in biodegradable and biocompatible poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP). These NP stabilized the oil droplets (Miglyol) containing an anti-inflammatory drug, calcitriol (CAL). The influence of the API on the physico-chemical properties of these emulsions were studied. Emulsions formulated with or without API had a similar macroscopic and microscopic structure, as well as interfacial properties, and they exhibited a good stability for at least 55 days. The emulsions did not alter the viability of human keratinocytes (HaCaT cell line) after 2 and 5 days of exposure to NP concentrations equivalent to efficient API dosages. Thus, these new Pickering emulsions appear as a promising multidrug delivery system for the treatment of chronical inflammatory skin diseases.


Assuntos
Nanopartículas , Humanos , Emulsões/química , Nanopartículas/química , Tamanho da Partícula
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