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1.
Immunity ; 53(4): 824-839.e10, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33053331

RESUMEN

CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.


Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Transcriptoma/inmunología , Microambiente Tumoral/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
2.
Crit Care Med ; 49(9): 1513-1523, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-33900216

RESUMEN

RATIONALE: There is an unmet need to improve the description of the state of T-cell exhaustion in patients with sepsis, its reproducibility and correlation with the outcomes before including immunotherapy (like recombinant interleukin-7 or immune checkpoint inhibitors) in the therapeutic armamentarium against sepsis. DESIGN: Observational prospective study. SETTING: Two ICUs in a teaching hospital (France). PATIENTS: Eighty patients with sepsis admitted to the ICU. INTERVENTIONS: Quantification of CD4+ and CD8+ T-cell exhaustion at days 1 and 3. Quantification of the exhaustion markers (programmed death [PD]-1, 2B4, and cluster of differentiation [CD] 160) on T cells, the number of CD4+ regulatory T cells (CD3+ CD4+ CD25hi CD127Lo cells), and the phorbol myristate acetate/ionomycin/ionomycin-induced cytokines production (tumor necrosis factor-α, interleukin-2, and interferon-γ). MEASUREMENTS AND MAIN RESULTS: Using unsupervised clustering analysis, patients could be split in three clusters according to their dominant pattern expression of exhaustion markers on CD8+ T cells (i.e., 2B4lowPD-1lowCD160low, 2B4hiPD-1hiCD160low, and 2B4hiPD-1lowCD160hi) regardless of their underlying morbidities. Only 2B4hiPD-1hiCD160low CD8+ T cells had cytokine production defect, whereas 2B4hi PD-1lowCD160hi pattern correlated with cytokine overproduction. Patients with a predominant "highly activated" 2B4hiPD-1lowCD160hi pattern did not develop secondary bacterial infections. By multivariate analysis, Simplified Acute Physiology Score 2 gravity score at day 1 (p = 0.003) and patterns of exhaustion markers on CD8+ T cells (p = 0.03) were associated with the risk of death. Neither the level of CD4+ regulatory T cells nor the CD4+ exhaustion patterns were associated with the outcomes. CONCLUSIONS: Easy-to-use multicolor flow cytometry assessing 2B4, PD-1, and CD160 expression on CD8+ T cells at day 1 identifies septic patients with poor outcome and discriminates patient subsets in who immunomodulatory drugs should be tested.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Sepsis/complicaciones , Anciano , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Femenino , Francia , Humanos , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Estudios Prospectivos , Reproducibilidad de los Resultados , Sepsis/metabolismo , Índice de Severidad de la Enfermedad
3.
BMC Cancer ; 19(1): 809, 2019 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-31412798

RESUMEN

BACKGROUND: Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers. METHODS: We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event. RESULTS: Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm3 (HR, 3.30, p <  0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10- 4 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection. CONCLUSIONS: Consolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD4-Positivos/patología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Región Variable de Inmunoglobulina/genética , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación , Neoplasia Residual , Pronóstico , Rituximab/efectos adversos , Rituximab/uso terapéutico , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico
4.
J Vis Commun Med ; 38(1-2): 117-8, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26203944

RESUMEN

The field of Medical and Scientific Illustration in the United States is large and constantly changing. In 1974, when the author began his studies, everything about the field was different. At the time, a student in the U.S. could go to a number of Universities (4 year) or Colleges (2 year) to study this subject. More than forty years later, only a few programs still offer similar programs of study. The Rochester Institute of Technology (RIT), where the author is a professor and Randolph Community College in North Carolina are all that remain from the more than ten that had operated. These two programs are very different from one another and there is not adequate space in this article to expand on these differences. Program details can be found online at: http://cias.rit.edu/schools/photographic-arts-sciences/undergraduate-biomedical-photographic-communications.


Asunto(s)
Ilustración Médica/educación , Humanos , Fotograbar/educación , Red Social , Estados Unidos
5.
J Vis Commun Med ; 37(3-4): 116-21, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25427770

RESUMEN

Michael Peres has become a lead in the field of photomicrography and this article gives an account of his journey as a developing professional.


Asunto(s)
Ilustración Médica , Fotomicrografía , Educación Profesional
6.
HLA ; 103(4): e15399, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38568109

RESUMEN

The novel allele HLA-B*44:48:02 differs from HLA-B*44:48:01 by one synonymous nucleotide substitution in exon 3.


Asunto(s)
Antígenos HLA-B , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-B/genética
7.
HLA ; 103(4): e15400, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38568113

RESUMEN

The novel allele HLA-C*07:02:147 differs from HLA-C*07:02:01:01 by one synonymous nucleotide substitution in exon 2.


Asunto(s)
Genes MHC Clase I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Exones/genética , Nucleótidos
8.
HLA ; 103(4): e15406, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38568116

RESUMEN

The novel allele HLA-A*36:14 differs from HLA-A*36:01:01:01 by one non-synonymous nucleotide substitution in exon 4.


Asunto(s)
Antígenos HLA-A , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genética
9.
HLA ; 103(4): e15412, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38568180

RESUMEN

The novel allele HLA-DRB1*03:210 differs from HLA-DRB1*03:01:01:01 by one non-synonymous nucleotide substitution in exon 3.


Asunto(s)
Nucleótidos , Humanos , Alelos , Cadenas HLA-DRB1/genética , Exones/genética , Análisis de Secuencia de ADN
10.
HLA ; 103(4): e15413, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38575349

RESUMEN

The novel allele HLA-DRB1*11:323 differs from HLA-DRB1*11:01:02:01 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Nucleótidos , Humanos , Cadenas HLA-DRB1/genética , Alelos , Exones/genética , Análisis de Secuencia de ADN
11.
HLA ; 103(4): e15408, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38575359

RESUMEN

The novel allele HLA-A*30:01:23 differs from HLA-A*30:01:01:01 by one synonymous nucleotide substitution in exon 2.


Asunto(s)
Antígenos HLA-A , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genética
12.
HLA ; 103(4): e15409, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38575362

RESUMEN

The novel allele HLA-DPB1*1467:01 differs from HLA-DPB1*09:01:01:01 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Secuencia de Bases , Humanos , Alelos , Cadenas beta de HLA-DP/genética , Exones/genética , Análisis de Secuencia de ADN
13.
HLA ; 102(3): 363-365, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37329308

RESUMEN

The novel allele HLA-B*44:369 differs from HLA-B*44:02:01:01 by one non-synonymous nucleotide substitution in exon 3.


Asunto(s)
Antígenos HLA-B , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-B/genética
14.
HLA ; 102(3): 367-368, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37329314

RESUMEN

The novel allele HLA-B*53:01:30 differs from HLA-B*53:01:01:01 by one synonymous nucleotide substitution in exon 3.


Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Exones/genética , Análisis de Secuencia de ADN
15.
HLA ; 102(1): 114-115, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36932819

RESUMEN

The novel allele HLA-DRB1*16:71 differs from HLA-DRB1*16:01:01:01 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Nucleótidos , Humanos , Cadenas HLA-DRB1/genética , Alelos , Exones/genética , Análisis de Secuencia de ADN
16.
HLA ; 102(1): 86-88, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36965123

RESUMEN

The novel allele HLA-B*56:91 differs from HLA-B*56:33 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Antígenos HLA-B , Humanos , Alelos , Prueba de Histocompatibilidad , Antígenos HLA-B/genética , Exones/genética , Análisis de Secuencia de ADN
17.
HLA ; 102(1): 116-117, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36908265

RESUMEN

The novel allele HLA-DRB5*02:35 differs from HLA-DRB5*02:02:01 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Cadenas HLA-DRB5 , Humanos , Cadenas HLA-DRB5/genética , Alelos , Exones/genética , Análisis de Secuencia de ADN
18.
HLA ; 102(4): 536-538, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37381693

RESUMEN

The novel allele HLA-C*07:1058 differs from HLA-C*07:02:01:01 by one non-synonymous nucleotide substitution in exon 4.


Asunto(s)
Genes MHC Clase I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Prueba de Histocompatibilidad , Exones/genética , Análisis de Secuencia de ADN
19.
HLA ; 102(2): 214-216, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37143376

RESUMEN

The novel allele HLA-A*11:443 differs from HLA-A*11:01:01:01 by one non-synonymous nucleotide substitution in exon 2.


Asunto(s)
Antígenos HLA-A , Humanos , Alelos , Prueba de Histocompatibilidad , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genética
20.
Front Med (Lausanne) ; 10: 1224865, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37706025

RESUMEN

Background: The COVID-19 pandemic caused a wave of acute respiratory distress syndrome (ARDS) with a high in-hospital mortality, especially in patients requiring invasive mechanical ventilation. Wharton Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) may counteract the pulmonary damage induced by the SARS-CoV-2 infection through pro-angiogenic effects, lung epithelial cell protection, and immunomodulation. Methods: In this randomized, double-blind, placebo-controlled phase 2a trial, adult patients receiving invasive mechanical ventilation for SARS-CoV-2 induced moderate or severe ARDS were assigned to receive 1 intravenous infusion of 1 × 106 WJ-MSCs/kg or placebo within 48 h of invasive ventilation followed by 2 infusions of 0.5 × 106 WJ-MSCs/kg or placebo over 5 days. The primary endpoint was the percentage of patients with a PaO2/FiO2 > 200 on day 10. Results: Thirty patients were included from November 2020 to May 2021, 15 in the WJ-MSC group and 15 in the placebo group. We did not find any significant difference in the PaO2/FiO2 ratio at day 10, with 18 and 15% of WJ-MSCs and placebo-treated patients reaching a ratio >200, respectively. Survival did not differ in the 2 groups with a 20% mortality rate at day 90. While we observed a higher number of ventilation-free days at 28 days in the WJ-MSC arm, this difference was not statistically significant (median of 11 (0-22) vs. 0 (0-18), p = 0.2). The infusions were well tolerated, with a low incidence of anti-HLA alloimmunization after 90 days. Conclusion: While treatment with WJ-MSCs appeared safe and feasible in patients with SARS-CoV2 moderate or severe ARDS in this phase 2a trial, the treatment was not associated with an increased percentage of patients with P/F > 200 at 10d, nor did 90 day mortality improve in the treated group. Clinical trial registration: https://beta.clinicaltrials.gov/study/NCT04625738, identifier NCT04625738.

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