Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 187(15): 4078-4094.e21, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38897196

RESUMEN

Reversing CD8+ T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. In chronic settings, only 4-1BB stimulation conferred antiviral activity. In HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV infection.


Asunto(s)
Linfocitos T CD8-positivos , Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis B Crónica/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Animales , Receptores OX40/metabolismo , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Antígenos CD/metabolismo
2.
Nat Immunol ; 25(4): 633-643, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38486021

RESUMEN

Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8+ T cells are essential for combating severe infections, whereas CD4+ T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies.


Asunto(s)
COVID-19 , Vacunas , Humanos , Animales , Ratones , SARS-CoV-2 , Linfocitos T CD8-positivos , COVID-19/prevención & control , Anticuerpos , Vacunación , Anticuerpos Antivirales , Anticuerpos Neutralizantes
3.
Immunity ; 54(9): 2089-2100.e8, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34469774

RESUMEN

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.


Asunto(s)
Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Interleucina-2/inmunología , Macrófagos del Hígado/inmunología , Animales , Hepatitis B/inmunología , Tolerancia Inmunológica/inmunología , Ratones , Ratones Transgénicos
4.
Cell ; 161(3): 486-500, 2015 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-25892224

RESUMEN

Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae. Hepatocellular antigen recognition triggers effector functions in a diapedesis-independent manner and is inhibited by the processes of sinusoidal defenestration and capillarization that characterize liver fibrosis. These findings reveal the dynamic behavior whereby CD8 TE control hepatotropic pathogens and suggest how liver fibrosis might reduce CD8 TE immune surveillance toward infected or transformed hepatocytes.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Virus de la Hepatitis B/fisiología , Hepatitis B/inmunología , Hígado/inmunología , Monitorización Inmunológica , Animales , Movimiento Celular , Células Endoteliales/metabolismo , Hepatitis B/patología , Hepatocitos/metabolismo , Ácido Hialurónico/metabolismo , Hígado/citología , Cirrosis Hepática , Ratones , Ratones Endogámicos C57BL , Adhesividad Plaquetaria , Organismos Libres de Patógenos Específicos
5.
Nature ; 574(7777): 200-205, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31582858

RESUMEN

The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Virus de la Hepatitis B/inmunología , Hepatocitos/inmunología , Hepatocitos/virología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Cromatina/metabolismo , Femenino , Hepatitis B/tratamiento farmacológico , Hepatitis B/inmunología , Hepatitis B/virología , Humanos , Tolerancia Inmunológica , Interleucina-2/inmunología , Interleucina-2/uso terapéutico , Macrófagos del Hígado/inmunología , Activación de Linfocitos , Masculino , Ratones , Transcriptoma/genética
7.
Immunity ; 38(4): 782-91, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23601687

RESUMEN

Secondary lymphoid organ stromal cells comprise different subsets whose origins remain unknown. Herein, we exploit a genetic lineage-tracing approach to show that splenic fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs), marginal reticular cells (MRCs), and mural cells, but not endothelial cells, originate from embryonic mesenchymal progenitors of the Nkx2-5(+)Islet1(+) lineage. This lineage include embryonic mesenchymal cells with lymphoid tissue organizer (LTo) activity capable also of supporting ectopic lymphoid-like structures and a subset of resident spleen stromal cells that proliferate and regenerate the splenic stromal microenvironment following resolution of a viral infection. These findings identify progenitor cells that generate stromal diversity in spleen development and repair and suggest the existence of multipotent stromal progenitors in the adult spleen with regenerative capacity.


Asunto(s)
Células Dendríticas Foliculares/metabolismo , Fibroblastos/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas con Homeodominio LIM/metabolismo , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Bazo/patología , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Células Dendríticas Foliculares/patología , Fibroblastos/patología , Proteína Homeótica Nkx-2.5 , Coriomeningitis Linfocítica/fisiopatología , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Regeneración , Células del Estroma/metabolismo , Células del Estroma/patología
8.
Bioorg Med Chem Lett ; 73: 128904, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35868496

RESUMEN

Chronic hepatitis B (CHB) is a major worldwide public health problem and novel anti-HBV therapies preventing liver disease progression to cirrhosis and hepatocellular carcinoma are urgently needed. Over the last several years, capsid assembly modulators (CAM) have emerged as clinically effective anti-HBV agents which can inhibit HBV replication in CHB patients. As part of a drug discovery program aimed at obtaining novel CAM endowed with high in vitro and in vivo antiviral activity, we identified a novel series of sulfamoylbenzamide (SBA) derivatives. Compound 10, one of the most in vitro potent SBA-derived CAM discovered to date, showed excellent pharmacokinetics in mice suitable for oral dosing. When studied in a transgenic mouse model of hepatic HBV replication, it was considerably more potent than NVR 3-778, the first sulfamoylbenzamide (SBA) CAM that entered clinical trials for CHB, at reducing viral replication in a dose-dependent fashion. We present herein the discovery process, the SAR analysis and the pre-clinical profile of this novel SBA CAM.


Asunto(s)
Antivirales , Cápside , Animales , Antivirales/farmacocinética , Proteínas de la Cápside , Virus de la Hepatitis B , Ratones , Ensamble de Virus , Replicación Viral
10.
J Hepatol ; 67(3): 543-548, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28483675

RESUMEN

BACKGROUND & AIMS: Besides secreting pro-inflammatory cytokines, chemokines and effector molecules, effector CD8+ T cells that arise upon acute infection with certain viruses have been shown to produce the regulatory cytokine interleukin (IL)-10 and, therefore, contain immunopathology. Whether the same occurs during acute hepatitis B virus (HBV) infection and role that IL-10 might play in liver disease is currently unknown. METHODS: Mouse models of acute HBV pathogenesis, as well as chimpanzees and patients acutely infected with HBV, were used to analyse the role of CD8+ T cell-derived IL-10 in liver immunopathology. RESULTS: Mouse HBV-specific effector CD8+ T cells produce significant amounts of IL-10 upon in vivo antigen encounter. This is corroborated by longitudinal data in a chimpanzee acutely infected with HBV, where serum IL-10 was readily detectable and correlated with intrahepatic CD8+ T cell infiltration and liver disease severity. Unexpectedly, mouse and human CD8+ T cell-derived IL-10 was found to act in an autocrine/paracrine fashion to enhance IL-2 responsiveness, thus preventing antigen-induced HBV-specific effector CD8+ T cell apoptosis. Accordingly, the use of mouse models of HBV pathogenesis revealed that the IL-10 produced by effector CD8+ T cells promoted their own intrahepatic survival and, thus supported, rather than suppressed liver immunopathology. CONCLUSION: Effector CD8+ T cell-derived IL-10 enhances acute liver immunopathology. Altogether, these results extend our understanding of the cell- and tissue-specific role that IL-10 exerts in immune regulation. Lay summary: Interleukin-10 is mostly regarded as an immunosuppressive cytokine. We show here that HBV-specific CD8+ T cells produce IL-10 upon antigen recognition and that this cytokine enhances CD8+ T cell survival. As such, IL-10 paradoxically promotes rather than suppresses liver disease.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interleucina-10/fisiología , Hígado/inmunología , Enfermedad Aguda , Animales , Apoptosis , Virus de la Hepatitis B/inmunología , Humanos , Interleucina-2/farmacología , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Pan troglodytes
12.
Nature ; 465(7301): 1079-83, 2010 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-20577213

RESUMEN

Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.


Asunto(s)
Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/virología , Macrófagos/inmunología , Infecciones por Rhabdoviridae/inmunología , Vesiculovirus/inmunología , Animales , Sistema Nervioso Central/citología , Células Dendríticas/inmunología , Inyecciones , Interferón Tipo I/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inervación , Macrófagos/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Parálisis/complicaciones , Parálisis/virología , Nervios Periféricos/virología , Receptor de Interferón alfa y beta/deficiencia , Infecciones por Rhabdoviridae/complicaciones , Infecciones por Rhabdoviridae/virología , Tasa de Supervivencia , Virus de la Estomatitis Vesicular Indiana/inmunología , Virus de la Estomatitis Vesicular Indiana/patogenicidad , Virus de la Estomatitis Vesicular Indiana/fisiología , Virus de la Estomatitis Vesicular New Jersey/inmunología , Virus de la Estomatitis Vesicular New Jersey/patogenicidad , Virus de la Estomatitis Vesicular New Jersey/fisiología , Vesiculovirus/patogenicidad , Vesiculovirus/fisiología
13.
Hepatology ; 59(6): 2331-43, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24452456

RESUMEN

UNLABELLED: Aberrant DNA replication induced by deregulated or excessive proliferative stimuli evokes a "replicative stress response" leading to cell cycle restriction and/or apoptosis. This robust fail-safe mechanism is eventually bypassed by transformed cells, due to ill-defined epistatic interactions. The COP9 signalosome (CSN) is an evolutionarily conserved regulator of cullin ring ligases (CRLs), the largest family of ubiquitin ligases in metazoans. Conditional inactivation of the CSN in several tissues leads to activation of S- or G2-phase checkpoints resulting in irreversible cell cycle arrest and cell death. Herein we ablated COPS5, the CSNs catalytic subunit, in the liver, to investigate its role in cell cycle reentry by differentiated hepatocytes. Lack of COPS5 in regenerating livers causes substantial replicative stress, which triggers a CDKN2A-dependent genetic program leading to cell cycle arrest, polyploidy, and apoptosis. These outcomes are phenocopied by acute overexpression of c-Myc in COPS5 null hepatocytes of adult mice. CONCLUSION: We propose that combined control of proto-oncogene product levels and proteins involved in DNA replication origin licensing may explain the deleterious consequences of CSN inactivation in regenerating livers and provide insight into the pathogenic role of the frequently observed overexpression of the CSN in hepatocellular carcinoma.


Asunto(s)
Hepatocitos/fisiología , Regeneración Hepática , Complejos Multiproteicos/fisiología , Péptido Hidrolasas/fisiología , Animales , Complejo del Señalosoma COP9 , Replicación del ADN , Femenino , Genes myc , Genes p16 , Homeostasis , Hígado/fisiología , Hígado/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Poliploidía
14.
Proc Natl Acad Sci U S A ; 109(32): E2165-72, 2012 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-22753481

RESUMEN

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8(+) T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8(+) T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8(+) T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC. Antiplatelet therapy improved overall survival without causing significant side effects. In contrast, the same antiplatelet regimen had no antitumor effect when HCC was induced nonimmunologically by chronic exposure to a hepatotoxic chemical. The unprecedented observation that antiplatelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be key players in the pathogenesis of HBV-associated liver cancer and supports the notion that immune-mediated necroinflammatory reactions are an important cause of hepatocellular transformation during chronic hepatitis.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/prevención & control , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/inmunología , Neoplasias Hepáticas/prevención & control , Inhibidores de Agregación Plaquetaria/farmacología , Análisis de Varianza , Animales , Aspirina , Linfocitos T CD8-positivos/efectos de los fármacos , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Clopidogrel , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Hepatitis B Crónica/patología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Ticlopidina/análogos & derivados
15.
J Immunol ; 188(7): 3217-22, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22379027

RESUMEN

B cells require MHC class II (MHC II)-restricted cognate help and CD40 engagement by CD4(+) T follicular helper (T(FH)) cells to form germinal centers and long-lasting Ab responses. Invariant NKT (iNKT) cells are innate-like lymphocytes that jumpstart the adaptive immune response when activated by the CD1d-restricted lipid α-galactosylceramide (αGalCer). We previously observed that immunization of mice lacking CD4(+) T cells (MHC II(-/-)) elicits specific IgG responses only when protein Ags are mixed with αGalCer. In this study, we investigated the mechanisms underpinning this observation. We find that induction of Ag-specific Ab responses in MHC II(-/-) mice upon immunization with protein Ags mixed with αGalCer requires CD1d expression and CD40 engagement on B cells, suggesting that iNKT cells provide CD1d-restricted cognate help for B cells. Remarkably, splenic iNKT cells from immunized MHC II(-/-) mice display a typical CXCR5(hi)programmed death-1(hi)ICOS(hi)Bcl-6(hi) T(FH) phenotype and induce germinal centers. The specific IgG response induced in MHC II(-/-) mice has shorter duration than that developing in CD4-competent animals, suggesting that iNKT(FH) cells preferentially induce transient rather than long-lived Ab responses. Together, these results suggest that iNKT cells can be co-opted into the follicular helper function, yet iNKT(FH) and CD4(+) T(FH) cells display distinct helper features, consistent with the notion that these two cell subsets play nonredundant functions throughout immune responses.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Cooperación Linfocítica/inmunología , Células T Asesinas Naturales/inmunología , Traslado Adoptivo , Animales , Formación de Anticuerpos , Antígenos CD1d/inmunología , Linfocitos B/citología , Linfocitos B/trasplante , Galactosilceramidas/farmacología , Genes MHC Clase II , Centro Germinal/citología , Inmunización , Inmunoglobulina G/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Organismos Libres de Patógenos Específicos , Linfocitos T Colaboradores-Inductores
16.
JHEP Rep ; 6(5): 101038, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38694959

RESUMEN

Background & Aims: Liver diseases resulting from chronic HBV infection are a significant cause of morbidity and mortality. Vaccines that elicit T-cell responses capable of controlling the virus represent a treatment strategy with potential for long-term effects. Here, we evaluated vaccines that induce the activity of type I natural killer T (NKT) cells to limit viral replication and license stimulation of conventional antiviral T-cells. Methods: Vaccines were prepared by conjugating peptide epitopes to an NKT-cell agonist to promote co-delivery to antigen-presenting cells, encouraging NKT-cell licensing and stimulation of T cells. Activity of the conjugate vaccines was assessed in transgenic mice expressing the complete HBV genome, administered intravenously to maximise access to NKT cell-rich tissues. Results: The vaccines induced only limited antiviral activity in unmanipulated transgenic hosts, likely attributable to NKT-cell activation as T-cell tolerance to viral antigens is strong. However, in a model of chronic hepatitis B involving transfer of naive HBcAg-specific CD8+ T cells into the transgenic mice, which typically results in specific T-cell dysfunction without virus control, vaccines containing the targeted HBcAg epitope induced prolonged antiviral activity because of qualitatively improved T-cell stimulation. In a step towards a clinical product, vaccines were prepared using synthetic long peptides covering clusters of known HLA-binding epitopes and shown to be immunogenic in HLA transgenic mice. Predictions based on HLA distribution suggest a product containing three selected SLP-based vaccines could give >90 % worldwide coverage, with an average of 3.38 epitopes targeted per individual. Conclusions: The novel vaccines described show promise for further clinical development as a treatment for chronic hepatitis B. Impact and Implications: Although there are effective prophylactic vaccines for HBV infection, it is estimated that 350-400 million people worldwide have chronic hepatitis B, putting these individuals at significant risk of life-threatening liver diseases. Therapeutic vaccination aimed at activating or boosting HBV-specific T-cell responses holds potential as a strategy for treating chronic infection, but has so far met with limited success. Here, we show that a glycolipid-peptide conjugate vaccine designed to coordinate activity of type I NKT cells alongside conventional antiviral T cells has antiviral activity in a mouse model of chronic infection. It is anticipated that a product based on a combination of three such conjugates, each prepared using long peptides covering clusters of known HLA-binding epitopes, could be developed further as a treatment for chronic hepatitis B with broad global HLA coverage.

17.
J Hepatol ; 59(5): 1135-8, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23742914

RESUMEN

Previous studies in mouse models of self-limited viral hepatitis showed that platelets contribute to acute liver damage by promoting the intrahepatic accumulation of virus-specific CD8 T cells and, secondarily, virus-non-specific inflammatory cells. Built on these observations, a recent preclinical study took advantage of a previously established hepatitis B virus (HBV) transgenic mouse model of immune-mediated chronic hepatitis that progresses to hepatocellular carcinoma (HCC), to demonstrate that clinically achievable doses of the anti-platelet drugs aspirin and clopidogrel - administered continuously after the onset of liver disease - can prevent hepatocarcinogenesis and greatly improve overall survival. These outcomes were preceded by and associated with reduced hepatic accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells, reduced hepatocellular injury and hepatocellular proliferation, and reduced severity of liver fibrosis. The observation that anti-platelet therapy inhibits HCC development identifies platelets as key players in the pathogenesis of HBV-associated liver cancer and supports the notion that a sustained immune-mediated necroinflammatory liver disease is sufficient to trigger HCC. The results abovementioned and their clinical implications are discussed in this report.


Asunto(s)
Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/virología , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/virología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Animales , Aspirina/farmacología , Aspirina/uso terapéutico , Plaquetas/efectos de los fármacos , Plaquetas/patología , Linfocitos T CD8-positivos/patología , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Clopidogrel , Modelos Animales de Enfermedad , Hepatitis B Crónica/patología , Humanos , Neoplasias Hepáticas/patología , Ratones , Inhibidores de Agregación Plaquetaria/farmacología , Ticlopidina/análogos & derivados , Ticlopidina/farmacología , Ticlopidina/uso terapéutico
18.
PLoS Pathog ; 7(6): e1002061, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21655107

RESUMEN

Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.


Asunto(s)
Hepatitis B/patología , Hepatocitos/metabolismo , Macrófagos del Hígado/fisiología , Hígado/patología , Animales , Antiinflamatorios/farmacología , Apoptosis , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacología , Linfocitos T CD8-positivos/metabolismo , Ácido Clodrónico/administración & dosificación , Ácido Clodrónico/farmacología , Modelos Animales de Enfermedad , Gadolinio/farmacología , Proteínas HMGB/sangre , Proteínas HMGB/metabolismo , Hepatitis B/inmunología , Hepatitis B/virología , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/fisiología , Hepatocitos/inmunología , Hepatocitos/patología , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/inmunología , Liposomas , Hígado/inmunología , Hígado/metabolismo , Hígado/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neutrófilos/fisiología , ARN Mensajero/genética , Receptores Depuradores/metabolismo , Factores de Tiempo
19.
EMBO Mol Med ; 15(5): e17580, 2023 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-36946379

RESUMEN

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.


Asunto(s)
Inmunidad Adaptativa , Antivirales , Tratamiento Farmacológico de COVID-19 , Lactamas , Animales , Ratones , COVID-19/inmunología , SARS-CoV-2 , Antivirales/administración & dosificación , Inmunidad Adaptativa/efectos de los fármacos , Lactamas/administración & dosificación , Células T de Memoria/inmunología , Linfocitos B/inmunología , Ratones Endogámicos C57BL
20.
Nat Med ; 11(11): 1167-9, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16258538

RESUMEN

We found that platelet depletion reduces intrahepatic accumulation of virus-specific cytotoxic T lymphocytes (CTLs) and organ damage in mouse models of acute viral hepatitis. Transfusion of normal but not activation-blocked platelets in platelet-depleted mice restored accumulation of CTLs and severity of disease. In contrast, anticoagulant treatment that prevented intrahepatic fibrin deposition without reducing platelet counts did not avert liver injury. Thus, activated platelets contribute to CTL-mediated liver immunopathology independently of procoagulant function.


Asunto(s)
Plaquetas/metabolismo , Hepatopatías/inmunología , Hepatopatías/patología , Hígado/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Recuento de Células , Citotoxicidad Inmunológica/genética , Modelos Animales de Enfermedad , Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hígado/patología , Hígado/virología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Activación Plaquetaria , Índice de Severidad de la Enfermedad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA