RESUMEN
BACKGROUND: Treatment with anti-CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA-based COVID-19 vaccines in children aged 5-18 years undergoing rituximab treatment compared to healthy matched children. METHODS: Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5-18 years under rituximab treatment who had received two mRNA-based SARS-CoV-2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS-CoV-2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. RESULTS: The rituximab-treated group exhibited significantly lower levels of antibodies specific to the anti-receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p = .008). However, patients with a rituximab-to-vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti-N antibody levels) had a high level of anti-RBD antibodies. CONCLUSION: A past infection with SARS-CoV-2 may induce anti-RBD-specific memory B cells that can be re-activated by SARS-CoV-2 vaccination, even after rituximab-induced B-cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS-CoV-2 infection.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Rituximab , SARS-CoV-2 , Humanos , Rituximab/uso terapéutico , Niño , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Femenino , Masculino , Adolescente , Preescolar , Estudios Prospectivos , Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , Inmunogenicidad Vacunal , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
BACKGROUND: The burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH - even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR'HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls. METHODS: We will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls. DISCUSSION: The SHINGR'HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).
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Infecciones por VIH , Vacuna contra el Herpes Zóster , Herpes Zóster , Neuralgia Posherpética , Humanos , Persona de Mediana Edad , Anciano , Neuralgia Posherpética/prevención & control , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Calidad de Vida , Herpes Zóster/epidemiología , Herpesvirus Humano 3 , Vacunas Sintéticas , Inmunidad , Estudios Multicéntricos como AsuntoRESUMEN
A recurrent question is whether transient reactions to vaccines translate into better immune responses. Using clinical data from 2 large phase 3 studies of the recombinant zoster vaccine, we observed a small but statistically significant association between the intensity of a frequent side effect (pain) after vaccination and immune responses to vaccination. However, despite the statistical correlation, the impact on the immune response is so small, and the immune response in individuals without pain already sufficient, that pain cannot be a surrogate marker for an appropriate immune response. Reactogenicity cannot be used to predict immunity after vaccination.
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Vacuna contra el Herpes Zóster , Herpes Zóster , Humanos , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Farmacéuticos , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/efectos adversos , Inmunogenicidad Vacunal , Dolor/inducido químicamente , Vacunas Sintéticas/efectos adversosRESUMEN
BACKGROUND: Patients treated with anti-CD20 therapy are particularly at risk of developing severe coronavirus disease 2019 (COVID-19); however, little is known regarding COVID-19 vaccine effectiveness in this population. METHODS: This prospective observational cohort study assesses humoral and T-cell responses after vaccination with 2 doses of mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (nâ =â 37), compared to immunocompetent individuals (nâ =â 22). RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4â T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8â T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). S-specific CD4â and CD8â T cells were polyfunctional but expressed more effector molecules in patients than in controls. During follow-up, 3 MS patients without SARS-CoV-2-specific antibody response had a mild breakthrough infection. One of them had no detectable S-specific T cells after vaccination. CONCLUSIONS: Our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of severe COVID-19.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Vacunas Virales , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Estudios Prospectivos , ARN Mensajero , Rituximab , SARS-CoV-2 , VacunaciónRESUMEN
SUMMARY: Untargeted liquid chromatography-mass spectrometry (LC-MS) profiling assays are capable of measuring thousands of chemical compounds in a single sample, but unreliable feature extraction and metabolite identification remain considerable barriers to their interpretation and usefulness. peakPantheR (Peak Picking and ANnoTation of High-resolution Experiments in R) is an R package for the targeted extraction and integration of annotated features from LC-MS profiling experiments. It takes advantage of chromatographic and spectral databases and prior information of sample matrix composition to generate annotated and interpretable metabolic phenotypic datasets and power workflows for real-time data quality assessment. AVAILABILITY AND IMPLEMENTATION: peakPantheR is available via Bioconductor (https://bioconductor.org/packages/peakPantheR/). Documentation and worked examples are available at https://phenomecentre.github.io/peakPantheR.github.io/ and https://github.com/phenomecentre/metabotyping-dementia-urine. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Programas Informáticos , Espectrometría de Masas en Tándem , Cromatografía Liquida , Metabolómica , DocumentaciónRESUMEN
After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics. For example, they induce early activation (although at different levels) of innate immunity which then translates into higher antibody and cellular responses to the vaccine antigens. In addition, most of these adjuvants (e.g. MF59, AS03, AS04) clearly induce a wider breadth of adaptive responses able to confer protection against, for example, heterovariants of the influenza viruses (MF59, AS03) or against human papillomavirus strains not contained in the vaccine (AS04). Finally, the use of some of these adjuvants has contributed to significantly enhance the immune response and the efficacy and effectiveness of vaccines in the elderly who experience a waning of the immune responsiveness to infection and vaccination, as shown for MF59- or AS03-adjuvanted influenza vaccines and AS01-adjuvanted herpes zoster vaccine. These results, together with the track record of acceptable safety profiles of the adjuvanted vaccines, pave the way for the development of novel vaccines at the extremes of age and against infections with a high toll of morbidity and mortality. Here, we review the mechanisms associated with the performance of those adjuvanted vaccines in animal models and in humans through recent advances in systems vaccinology and biomarker discovery. We also provide some perspectives on remaining knowledge gaps but also on opportunities that could accelerate the development of new vaccines.
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Adyuvantes Inmunológicos/farmacología , Herpes Zóster/prevención & control , Inmunidad Celular/efectos de los fármacos , Inmunogenicidad Vacunal , Gripe Humana/prevención & control , Infecciones por Papillomavirus/prevención & control , Adyuvantes Inmunológicos/química , Anciano , Animales , Combinación de Medicamentos , Herpes Zóster/inmunología , Herpes Zóster/virología , Humanos , Inmunidad Humoral/efectos de los fármacos , Gripe Humana/inmunología , Gripe Humana/virología , Liposomas/administración & dosificación , Liposomas/química , Liposomas/inmunología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Polisorbatos/química , Polisorbatos/farmacología , Escualeno/química , Escualeno/farmacología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/microbiología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/microbiología , Vacunas Virales/administración & dosificación , Vacunas Virales/química , Vacunas Virales/inmunología , alfa-Tocoferol/química , alfa-Tocoferol/farmacologíaRESUMEN
BACKGROUND: SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches. METHODS: SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms. RESULTS: Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG. CONCLUSION: The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.
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COVID-19/inmunología , Citocinas/biosíntesis , Inflamación/etiología , Mucosa Nasal/inmunología , SARS-CoV-2 , Carga Viral , Adulto , Anciano , Anticuerpos Antivirales , COVID-19/virología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2/inmunologíaRESUMEN
The 3-O-desacyl-4'-monophosphoryl lipid A (MPL) activates immunity through Toll-like receptor 4 (TLR4) signaling. The Adjuvant System AS01 contains MPL and is used in the candidate malaria vaccine and the licensed zoster vaccine. Recent studies reported that AS01 adjuvant activity depends on a transient inflammation at the site of vaccination, but the role of stromal or structural cells in the adjuvant effect is unknown. We investigated this question in mouse models by assessing the role of TLR4 on hematopoietic versus resident structural cells during immunization with AS01-adjuvanted vaccines. We first established that TLR4-deficient animals had a reduced immune response to an AS01-adjuvanted vaccine. Using bone marrow chimera, we consistently found that Tlr4 expression in radio-sensitive cells, i.e., hematopoietic cells, was required for an optimal adjuvant effect on antibody and T-cell responses. At day 1 after injection, the pro-inflammatory reaction at the site of injection was strongly dependent on TLR4 signaling in hematopoietic cells. Similarly, activation of dendritic cells in muscle-draining lymph nodes was strictly associated with the radio-sensitive cells expressing Tlr4. Altogether, these data suggest that MPL-mediated TLR4-signaling in hematopoietic cells is critical in the mode of action of AS01.
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Adyuvantes Inmunológicos/farmacología , Células Madre Hematopoyéticas/inmunología , Lípido A/análogos & derivados , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/inmunología , Animales , Combinación de Medicamentos , Femenino , Células Madre Hematopoyéticas/citología , Humanos , Lípido A/farmacología , Masculino , Ratones , Ratones Noqueados , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptor Toll-Like 4/genética , Vacunas/farmacologíaRESUMEN
SUMMARY: As large-scale metabolic phenotyping studies become increasingly common, the need for systemic methods for pre-processing and quality control (QC) of analytical data prior to statistical analysis has become increasingly important, both within a study, and to allow meaningful inter-study comparisons. The nPYc-Toolbox provides software for the import, pre-processing, QC and visualization of metabolic phenotyping datasets, either interactively, or in automated pipelines. AVAILABILITY AND IMPLEMENTATION: The nPYc-Toolbox is implemented in Python, and is freely available from the Python package index https://pypi.org/project/nPYc/, source is available at https://github.com/phenomecentre/nPYc-Toolbox. Full documentation can be found at http://npyc-toolbox.readthedocs.io/ and exemplar datasets and tutorials at https://github.com/phenomecentre/nPYc-toolbox-tutorials.
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Metabolómica , Programas Informáticos , Documentación , Control de CalidadRESUMEN
The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
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Antígenos CD/inmunología , Homeostasis/fisiología , Gripe Humana/inmunología , Pulmón/inmunología , Células Mieloides/inmunología , Animales , Citocinas/biosíntesis , Homeostasis/inmunología , Humanos , Gripe Humana/patología , Pulmón/metabolismo , RatonesRESUMEN
The liposome-based adjuvant AS01 incorporates two immune stimulants, 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 is under investigation for use in several vaccines in clinical development. i.m. injection of AS01 enhances immune cell activation and dendritic cell (DC) Ag presentation in the local muscle-draining lymph node. However, cellular and Ag trafficking in the lymphatic vessels that connect an i.m. injection site with the local lymph node has not been investigated. The objectives of this study were: 1) to quantify the in vivo cellular immune response induced by AS01 in an outbred ovine model, 2) to develop a lymphatic cannulation model that directly collects lymphatic fluid draining the muscle, and 3) to investigate the function of immune cells entering and exiting the lymphatic compartments after s.c. or i.m. vaccination with AS01 administered with hepatitis B surface Ag (HBsAg). We show that HBsAg-AS01 induces a distinct immunogenic cellular signature within the blood and draining lymphatics following both immunization routes. We reveal that MHCII(high) migratory DCs, neutrophils, and monocytes can acquire Ag within muscle and s.c. afferent lymph, and that HBsAg-AS01 uniquely induces the selective migration of Ag-positive neutrophils, monocytes, and an MHCII(high) DC-like cell type out of the lymph node via the efferent lymphatics that may enhance Ag-specific immunity. We report the characterization of the immune response in the lymphatic network after i.m. and s.c. injection of a clinically relevant vaccine, all in real time using a dose and volume comparable with that administered in humans.
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Lípido A/análogos & derivados , Vasos Linfáticos/inmunología , Saponinas/inmunología , Animales , Combinación de Medicamentos , Antígenos de Superficie de la Hepatitis B/administración & dosificación , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Inyecciones Intramusculares , Inyecciones Subcutáneas , Lípido A/administración & dosificación , Lípido A/inmunología , Saponinas/administración & dosificación , OvinosRESUMEN
The TWIST1 bHLH transcription factor controls embryonic development and cancer processes. Although molecular and genetic analyses have provided a wealth of data on the role of bHLH transcription factors, very little is known on the molecular mechanisms underlying their binding affinity to the E-box sequence of the promoter. Here, we used an in silico model of the TWIST1/E12 (TE) heterocomplex and performed molecular dynamics (MD) simulations of its binding to specific (TE-box) and modified E-box sequences. We focused on (i) active E-box and inactive E-box sequences, on (ii) modified active E-box sequences, as well as on (iii) two box sequences with modified adjacent bases the AT- and TA-boxes. Our in silico models were supported by functional in vitro binding assays. This exploration highlighted the predominant role of protein side-chain residues, close to the heart of the complex, at anchoring the dimer to DNA sequences, and unveiled a shift towards adjacent ((-1) and (-1*)) bases and conserved bases of modified E-box sequences. In conclusion, our study provides proof of the predictive value of these MD simulations, which may contribute to the characterization of specific inhibitors by docking approaches, and their use in pharmacological therapies by blocking the tumoral TWIST1/E12 function in cancers.
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Elementos E-Box , Modelos Moleculares , Factor de Transcripción 3/química , Proteína 1 Relacionada con Twist/química , Secuencia de Bases , Sitios de Unión , Línea Celular , Humanos , Enlace de Hidrógeno , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Factor de Transcripción 3/metabolismo , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
The ASPP (apoptosis-stimulating protein of p53) family of proteins can function in the nucleus to modulate the transcriptional activity of p53, with ASPP1 and ASPP2 contributing to the expression of apoptotic target genes. In this study, we describe a new function for cytoplasmic ASPP1 in controlling YAP (Yes-associated protein)/TAZ. ASPP1 can inhibit the interaction of YAP with LATS1 (large tumor suppressor 1), a kinase that phosphorylates YAP/TAZ and promotes cytoplasmic sequestration and protein degradation. This function of ASPP1 therefore enhances nuclear accumulation of YAP/TAZ and YAP/TAZ-dependent transcriptional regulation. The consequence of YAP/TAZ activation by ASPP1 is to inhibit apoptosis, in part through the down-regulation of Bim expression, leading to resistance to anoikis and enhanced cell migration. These results reveal a potential oncogenic role for cytoplasmic ASPP1, in contrast to the tumor-suppressive activity described previously for nuclear ASPP1.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Fosfoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Anoicis , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Western Blotting , Adhesión Celular , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Hidroxiurea/farmacología , Inmunoprecipitación , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fosfoproteínas/genética , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción , Activación Transcripcional , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Oxylipins are potent lipid mediators demonstrated to initiate and regulate inflammation yet little is known regarding their involvement in the response to surgical trauma. As key modulators of the inflammatory response, oxylipins have the potential to provide novel insights into the physiological response to surgery and the pathophysiology of post-operative complications. We aimed to investigate the effects of major surgery on longitudinal oxylipin profile. METHODS: Adults patients undergoing elective laparoscopic or open colorectal resections were included. Primary outcomes were serum oxylipin profile quantified by ultra high-performance liquid chromatography-mass spectrometry, serum white cell count and C-reactive protein concentration. Serum samples were taken at three time-points: pre-operative (day zero), early post-operative (day one) and late post-operative (day four/five). RESULTS: Some 55 patients were included, of which 33 (60%) underwent surgery that was completed laparoscopically. Pre-operative oxylipin profiles were characterised by marked heterogeneity but surgery induced a common shift resulting in more homogeneity at the early post-operative time-point. By the late post-operative phase, oxylipin profiles were again highly variable. This evolution was driven by time-dependent changes in specific oxylipins. Notably, the levels of several oxylipins with anti-inflammatory properties (15-HETE and four regioisomers of DHET) were reduced at the early post-operative point before returning to baseline by the late post-operative period. In addition, levels of the pro-inflammatory 11-HETE rose in the early post-operative phase while levels of anti-thrombotic mediators (9-HODE and 13-HODE) fell; concentrations of all three oxylipins then remained fairly static from early to late post-operative phases. Compared to those undergoing laparoscopic surgery, patients undergoing open surgery had lower levels of some anti-inflammatory oxylipins (8,9-DHET and 17-HDoHE) in addition to reduced concentrations of anti-thrombotic mediators (9-HODE and 13-HODE) with increased concentration of their pro-thrombotic counterpart (TxB2). CONCLUSIONS: Serum oxylipin profile is modified by surgical intervention and may even be sensitive to the degree of surgical trauma and therefore represents a novel descriptor of the surgical systemic inflammatory response.
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Inflamación/sangre , Laparoscopía , Oxilipinas/sangre , Anciano , Proteína C-Reactiva/metabolismo , Demografía , Ácidos Grasos Insaturados/sangre , Femenino , Humanos , Recuento de Leucocitos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Factores de TiempoRESUMEN
Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.
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Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Método Doble Ciego , Femenino , Anticuerpos contra la Hepatitis B/sangre , Anticuerpos contra la Hepatitis B/inmunología , Humanos , Inmunoensayo/métodos , Mediciones Luminiscentes , Masculino , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
In addition to acting as a transcriptional cofactor for p53, ASPP1 has been shown to function in the cytoplasm to regulate the nuclear localization and activity of YAP/TAZ. We show here that the ability of ASPP1 to activate YAP results in the decreased expression of LATS2, which lowers the ability of p53 to induce p21, cell-cycle arrest and senescence. ASPP1 expression peaks in S-phase, and down-regulation of ASPP1 leads to a reduction in DNA synthesis and enhanced senescence in response to drugs that impede DNA replication. These activities of cytoplasmic ASPP1 in opposing p53-mediated p21 expression are in contrast to the role of nuclear ASPP1 in cooperating with p53 to induce the expression of apoptotic target genes, and may help to dampen p53 activity in normal cells.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Reguladoras de la Apoptosis/fisiología , Senescencia Celular/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Regulación de la Expresión Génica/fisiología , Proteína p53 Supresora de Tumor/fisiología , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/patología , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Senescencia Celular/efectos de los fármacos , Neoplasias del Colon/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Replicación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/fisiología , Dactinomicina/farmacología , Doxorrubicina/farmacología , Humanos , Hidroxiurea/farmacología , Proteínas Nucleares/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes de Fusión/fisiología , Factores de Transcripción/fisiología , Transcripción Genética , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/fisiologíaRESUMEN
Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.
Asunto(s)
Inmunidad Adaptativa/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Células Dendríticas/inmunología , Lípido A/análogos & derivados , Saponinas/administración & dosificación , Saponinas/inmunología , Vacunas/inmunología , Animales , Presentación de Antígeno/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Combinación de Medicamentos , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Lípido A/administración & dosificación , Lípido A/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , VacunaciónRESUMEN
Ubiquitin-specific peptidase 42 (USP42) is a deubiquitylating enzyme that can target p53 and contribute to the stabilization of p53 in response to stress. We now show that USP42 can also regulate transcription independently of p53. USP42 co-localized with RNA polymerase II (RNA Pol II) in nuclear foci, bound to histone H2B, and deubiquitylated H2B. Depletion of USP42 increased H2B ubiquitylation at a model promoter and decreased both basal and induced transcription from a number of promoters. These results are consistent with a role for USP42 in regulating transcription by deubiquitylating histones.