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1.
Front Immunol ; 15: 1352929, 2024.
Article in English | MEDLINE | ID: mdl-38545116

ABSTRACT

Background: HBe-antigen(Ag)-negative chronic hepatitis B virus (HBV) infection is characterized by little liver fibrosis progression and vigorous HBV-multispecific CD8+ T-cell response. Aims: To assess whether HBsAg level could discriminate different HBeAg-negative chronic HBV infection subtypes with dissimilar quality of HBV-specific CD8+ T-cell response. Methods: We recruited 63 HBeAg-negative chronic HBV infection patients in which indirect markers of liver inflammation/fibrosis, portal pressure, viral load (VL), and HBV-specific CD8+ cell effector function were correlated with HBsAg level. Results: A positive linear trend between HBsAg level and APRI, liver stiffness (LS), liver transaminases, and HBV VL, and a negative correlation with platelet count were observed. Frequency of cases with HBV-specific CD8+ T-cell proliferation against at least two HBV epitopes was higher in HBsAg < 1,000 IU/ml group. CD8+ T-cell expansion after HBVpolymerase456-63-specific stimulation was impaired in HBsAg > 1,000 IU/ml group, while the response against HBVcore18-27 was preserved and response against envelope183-91 was nearly abolished, regardless of HBsAg level. Cases with preserved HBVpolymerase456-63 CD8+ cell response had lower LS/duration of infection and APRI/duration of infection rates. HBV-polymerase456-63-specific CD8+ T-cell proliferation intensity was negatively correlated with LS/years of infection ratio. Conclusion: HBsAg > 1,000 IU/ml HBeAg-negative chronic HBV infection group shows indirect data of higher degree of inflammation, liver stiffness, and fibrosis progression speed, which are related to an impaired HBV-polymerase-specific CD8+ T-cell response.


Subject(s)
Gene Products, pol , Hepatitis B, Chronic , Humans , Hepatitis B virus/physiology , Hepatitis B Surface Antigens/genetics , Hepatitis B e Antigens/genetics , Inflammation , Liver Cirrhosis , CD8-Positive T-Lymphocytes , Alanine Transaminase , Phenotype
2.
iScience ; 27(1): 108666, 2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38155778

ABSTRACT

A rebalance between energy supply and demand in HBV-specific-CD8+ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8+ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.

4.
Aliment Pharmacol Ther ; 55(12): 1545-1559, 2022 06.
Article in English | MEDLINE | ID: mdl-35224746

ABSTRACT

BACKGROUND: Hepatitis B virus (HBV)-specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off-treatment HBV control in e-antigen-negative chronic hepatitis B (CHBe(-)). AIM: To predict this response with variables involved in T-cell exhaustion for use as a treatment stopping tool. METHODS: In NUC-treated CHBe(-) patients, we considered a functional response in cases with HBV-specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off-treatment follow-up according to LRM likelihood. RESULTS: We developed an LRM that predicted the presence of a proliferative type I cytokine-secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off-treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. CONCLUSIONS: Short-term low-level antigen exposure and early long-term NUC treatment influence the restoration of a functional HBV-specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off-treatment HBV control and HBsAg decline and loss.


Subject(s)
Hepatitis B, Chronic , Adult , Antiviral Agents/therapeutic use , CD8-Positive T-Lymphocytes , Cytokines , DNA, Viral/genetics , Epitopes , Hepatitis B Surface Antigens , Hepatitis B e Antigens , Hepatitis B virus/genetics , Humans , Treatment Outcome
5.
Cells ; 10(3)2021 03 03.
Article in English | MEDLINE | ID: mdl-33802622

ABSTRACT

Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.


Subject(s)
B7-H1 Antigen/genetics , Hepacivirus/immunology , Hepatitis C, Chronic/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Programmed Cell Death 1 Receptor/genetics , Receptors, Antigen, T-Cell, gamma-delta/genetics , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Gene Expression Regulation , Hepacivirus/pathogenicity , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Cellular/drug effects , Interleukins/genetics , Interleukins/immunology , Interleukins/therapeutic use , Lymphocyte Activation/drug effects , Precursor Cells, T-Lymphoid/drug effects , Precursor Cells, T-Lymphoid/immunology , Precursor Cells, T-Lymphoid/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Receptors, Antigen, T-Cell, gamma-delta/agonists , Receptors, Antigen, T-Cell, gamma-delta/immunology , Signal Transduction
6.
Cancers (Basel) ; 13(8)2021 Apr 16.
Article in English | MEDLINE | ID: mdl-33923463

ABSTRACT

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host's antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFß1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.

7.
World J Hepatol ; 12(10): 754-765, 2020 Oct 27.
Article in English | MEDLINE | ID: mdl-33200014

ABSTRACT

Hepatitis C virus (HCV) infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response. The antigen-specific cytotoxic T cell response is essential for keeping HCV under control, but during persistent infection, these cells become exhausted or even deleted. The exhaustion process is progressive and depends on the infection duration and level of antigenemia. During high antigenic load and long duration of infection, T cells become extremely exhausted and ultimately disappear due to apoptosis. The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines, such as transforming growth factor beta 1. This cytokine downregulates tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1), the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9 (known as 4-1BB). This impairment correlates with the low reactivity of T cells and an exhaustion phenotype. Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function. The process of TRAF1 loss and its in vitro recovery is hierarchical, and more affected by severe disease progression. In conclusion, TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV, and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

8.
J Virol ; 92(2)2018 01 15.
Article in English | MEDLINE | ID: mdl-29093082

ABSTRACT

Hepatitis C virus (HCV)-specific CD8+ T cells suffer a progressive exhaustion during persistent infection (PI) with HCV. This process could involve the positive immune checkpoint 4-1BB/4-1BBL through the loss of its signal transducer, TRAF1. To address this issue, peripheral HCV-specific CD8+ T cells (pentamer-positive [pentamer+]/CD8+ T cells) from patients with PI and resolved infection (RI) after treatment were studied. The duration of HCV infection and the liver fibrosis progression rate inversely correlated with the likelihood of detection of peripheral pentamer+/CD8+ cells. In PI, pentamer+/CD8+ cells had impaired antigen-specific reactivity that worsened when these cells were not detectable ex vivo Short/midduration PI was characterized by detectable peripheral PD-1+ CD127low TRAF1low cells. After triggering of T cell receptors (TCR), the TRAF1 level positively correlated with the levels of CD127, Mcl-1, and CD107a expression and proliferation intensity but negatively with PD-1 expression, linking TRAF1low to exhaustion. In vitro treatment with interleukin-7 (IL-7) upregulated TRAF1 expression, while treatment with transforming growth factor-ß1 (TGF-ß1) did the opposite, suggesting that the IL-7/TGF-ß1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, the serum TGF-ß1 concentration was higher in patients with PI than in patients with RI, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing the level of TRAF1 expression, IL-7 plus 4-1BBL treatment in vitro enhanced T cell reactivity in patients with short/midduration infection. However, in patients with long-lasting PI, anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, was necessary to reestablish T cell proliferation in individuals with slowly progressing liver fibrosis (slow fibrosers) but had no effect in rapid fibrosers. In conclusion, a peripheral hyporeactive TRAF1low HCV-specific CD8+ T cell response, restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8+ T cells are rarely detectable ex vivo, but treatment with IL-7, 4-1BBL, and anti-PD-L1 recovers their reactivity in vitro in slow fibrosers.IMPORTANCE Hepatitis C virus (HCV) infects 71 million people worldwide. Two-thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection, but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired, which could be due to the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. When the results are taken together, this work supports novel ways of restoring the specific CD8+ T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Hepacivirus/physiology , Hepatitis C/immunology , Hepatitis C/metabolism , Interleukin-7/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism , Aged , Disease Progression , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Female , Flow Cytometry , Gene Expression , Genotype , Hepatitis C/complications , Hepatitis C/virology , Humans , Liver Cirrhosis/etiology , Lymphocyte Activation/immunology , Male , Middle Aged , Phenotype , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Protein Binding , TNF Receptor-Associated Factor 1/metabolism
9.
Rev. esp. enferm. dig ; 108(10): 680-683, oct. 2016. tab, ilus
Article in Spanish | IBECS | ID: ibc-156757

ABSTRACT

El intervencionismo guiado por ecoendoscopia es un campo que se encuentra en rápido desarrollo. Recientemente se ha diseñado un nuevo prototipo de ecoendoscopio de visión frontal que pretende superar ciertas limitaciones de los ecoendoscopios convencionales (de visión oblicua). Se presenta a continuación el caso de un drenaje de pseudoquiste pancreático con un encoendoscopio de visión frontal llevado a cabo de forma exitosa. Si bien la difusión de este nuevo modelo de ecoendoscopio es aún escasa, las particularidades del mismo podrían contribuir a la ejecución con mayor sencillez de procedimientos terapéuticos habituales en la práctica clínica, así como a la consolidación de las potenciales aplicaciones del intervencionismo endoscópico (AU)


Interventional endoscopy is a field that continues to grow rapidly. A novel prototype forward-viewing echoendoscope (FV-EUS) has been recently developed in an attempt to overcome some of the limitations of conventional curved linear-array echoendoscopes (OV-EUS). We present a case of a successful endoscopic ultrasound-guided drainage of a pancreatic pseudocyst using a forward-viewing echoendoscope. Although the utilization use of this newly developed echoendoscope has not yet become widespread, its unique characteristics can help to easily perform routine therapeutic procedures and contribute to the expansion of interventional endoscopic utrasoundultrasound (AU)


Subject(s)
Humans , Female , Adult , Pancreatic Pseudocyst/surgery , Endosonography/methods , Drainage/methods , Postoperative Complications , Surgical Wound Dehiscence/surgery , Pancreatic Fistula/surgery
10.
Rev Esp Enferm Dig ; 108(10): 680-683, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27650893

ABSTRACT

Interventional endoscopy is a field that continues to grow rapidly. A novel prototype forward-viewing echoendoscope (FV-EUS) has been recently developed in an attempt to overcome some of the limitations of conventional curved linear-array echoendoscopes (OV-EUS). We present a case of a successful endoscopic ultrasound-guided drainage of a pancreatic pseudocyst using a forward-viewing echoendoscope. Although the utilization use of this newly developed echoendoscope has not yet become widespread, its unique characteristics can help to easily perform routine therapeutic procedures and contribute to the expansion of interventional endoscopic utrasoundultrasound.


Subject(s)
Drainage , Endoscopes, Gastrointestinal , Endosonography/methods , Pancreatic Pseudocyst/diagnostic imaging , Pancreatic Pseudocyst/therapy , Adult , Endoscopy, Gastrointestinal , Endosonography/instrumentation , Equipment Design , Female , Humans
11.
World J Gastroenterol ; 21(12): 3480-91, 2015 Mar 28.
Article in English | MEDLINE | ID: mdl-25834312

ABSTRACT

Hepatitis C virus (HCV)-specific cytotoxic T cell (CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response (SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in naïve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatment-induced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferon-free regimes, based on direct-acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Interferons/therapeutic use , Lymphocyte Activation/drug effects , T-Lymphocytes, Cytotoxic/drug effects , Animals , Hepacivirus/immunology , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology , Time Factors , Treatment Outcome , Viral Load
12.
World J Gastroenterol ; 20(13): 3418-30, 2014 Apr 07.
Article in English | MEDLINE | ID: mdl-24707125

ABSTRACT

Hepatitis C virus (HCV) infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma. HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control. Liver damage and disease progression during HCV infection are driven by both viral and host factors. Specifically, adaptive immune response carries out an essential task in controlling non-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery. HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion. To impair HCV-specific T cell reactivity, HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro- and anti-apoptotic proteins. In this review, the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.


Subject(s)
Adaptive Immunity , Hepatitis C/immunology , Antibodies/immunology , Apoptosis , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Separation , Chemokines/metabolism , Epitopes/immunology , Flow Cytometry , Gene Deletion , Humans , Immunity, Cellular , Immunity, Humoral , Inflammation , Mutation , Phenotype
13.
Cell Immunol ; 286(1-2): 31-8, 2013.
Article in English | MEDLINE | ID: mdl-24287274

ABSTRACT

Lower than 2-log viral-load (VL) decrease at week 12 (w12) of chronic hepatitis C (CHC) treatment with Peg-interferon/ribavirin has 100% negative predictive value (PV) of sustained virologic response (SVR), and this could be related with absence of HCV-specific cytotoxic T lymphocyte (CTL) response. In this study, percentage of cases with SVR, according to peripheral HCV-specific cytotoxic response at w12, was analysed (Group-1: detection(+), Group-2: detection(-)). SVR was higher in group-1 (93%) than in group-2 (47%) (p=0.003). An increase on HCV-specific CTL frequency between baseline and w12 and higher specific reactivity were observed in group-1 (p=0.011 and p=0.025). HCV-specific CTL detection at w12 correlated with level of VL decrease (p=0.016, r=0.389), and among HCV genotype-1 patients with either early or delayed virologic response (EDVR), 100% positive PV of SVR was observed. In summary, HCV-specific CTL detection at w12 of Peg-interferon/ribavirin treatment correlates with SVR and in EDVR genotype-1 cases predicts SVR.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/diagnosis , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , RNA, Viral/antagonists & inhibitors , Ribavirin/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , Adult , Biomarkers/analysis , Drug Therapy, Combination , Female , Hepacivirus/drug effects , Hepacivirus/immunology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , Lymphocyte Count , Male , Middle Aged , RNA, Viral/immunology , Recombinant Proteins/therapeutic use , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/virology , Treatment Outcome , Viral Load/drug effects
14.
World J Gastroenterol ; 19(12): 1877-89, 2013 Mar 28.
Article in English | MEDLINE | ID: mdl-23569333

ABSTRACT

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate naïve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.


Subject(s)
Hepatitis, Viral, Human/immunology , Immune Tolerance , T-Lymphocytes/pathology , Apoptosis/physiology , Apoptosis Regulatory Proteins/physiology , Bcl-2-Like Protein 11 , Cell Death/immunology , Hepatitis, Viral, Human/metabolism , Humans , Liver/immunology , Liver/pathology , Membrane Proteins/physiology , Proto-Oncogene Proteins/physiology
15.
Cell Immunol ; 269(2): 104-14, 2011.
Article in English | MEDLINE | ID: mdl-21481848

ABSTRACT

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8(+) cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8(+) cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1(-)/CD127(+) cells from RI cases was preserved, while it was impaired on PD-1(+)/CD127(-) cells from PI patients. PD1(+)/CD127(+) population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8(+) cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8(+) cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8(+) cells targeting the virus are PD-1(+)/CD127(-)/Bim(+) and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.


Subject(s)
Antigens, CD/metabolism , Apoptosis Regulatory Proteins/metabolism , Apoptosis/immunology , Hepatitis C, Chronic/immunology , Interleukin-7 Receptor alpha Subunit/metabolism , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , T-Lymphocytes, Cytotoxic/immunology , Adult , Amino Acid Chloromethyl Ketones/pharmacology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Apoptosis/drug effects , B7-H1 Antigen , Bcl-2-Like Protein 11 , Cell Count , Cell Proliferation/drug effects , Female , Humans , Immunophenotyping , Liver/immunology , Liver/pathology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Middle Aged , Programmed Cell Death 1 Receptor , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/physiology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Viral Load/immunology , Viral Nonstructural Proteins/immunology
16.
World J Gastroenterol ; 15(41): 5129-40, 2009 Nov 07.
Article in English | MEDLINE | ID: mdl-19891011

ABSTRACT

Hepatitis C virus (HCV)-specific CD8(+) T cells play an important role in the resolution of HCV infection. Nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the up-regulation of negative co-stimulatory molecules such us programmed death-1 (PD-1). This molecule is up-regulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8(+) T cells are exhausted with impairment of several effector mechanisms, such as: type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand (PD-L1). After this blockade, HCV-specific CD8(+) T cells reacquire their functionality. Nevertheless, functional restoration depends on PD-1 expression level. High PD-1-expressing intrahepatic HCV-specific CD8(+) T cells do not restore their effector abilities after PD-1/PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gC1q receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response against HCV to succeed in clearing the infection.


Subject(s)
Antigens, CD/metabolism , Apoptosis Regulatory Proteins/metabolism , Hepatitis C, Chronic/metabolism , T-Lymphocytes, Cytotoxic/metabolism , Acute Disease , B7-H1 Antigen , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Hepatitis C/metabolism , Hepatitis C/pathology , Hepatitis C, Chronic/pathology , Humans , Liver/metabolism , Liver/pathology , Programmed Cell Death 1 Receptor , T-Lymphocytes, Cytotoxic/pathology , Viral Core Proteins/metabolism
17.
World J Gastroenterol ; 14(47): 7149-59, 2008 Dec 21.
Article in English | MEDLINE | ID: mdl-19084927

ABSTRACT

Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1 alpha; MIP-1 alpha), CCL4 (MIP-1 beta), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-gamma-inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell alpha chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon gamma; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.


Subject(s)
Chemokines/physiology , Hepatitis C, Chronic/physiopathology , Liver/virology , Receptors, Chemokine/physiology , Animals , Antiviral Agents/therapeutic use , Disease Models, Animal , Hepacivirus/pathogenicity , Hepatitis C, Chronic/drug therapy , Humans , Liver/physiopathology , Treatment Outcome
18.
J Hepatol ; 47(5): 632-41, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17560677

ABSTRACT

BACKGROUND/AIMS: CXCR3 and CCR5 play a major role in recruiting cytotoxic T cells (Tc) and secreting secondary type 1 cytokines (Tc1) in the liver. HCV could impair their expression as a survival mechanism. The role of these chemokine receptors on CD8+ cells in chronic hepatitis C is analysed. METHODS: Serum, chemokines, peripheral blood and intrahepatic lymphocytes from chronic hepatitis C patients were studied. CXCR3/CCR5 expressing CD8+ cells were quantified by flow-cytometry. Serum chemokines concentration (CXCL10/CCL3) was measured by ELISA. Basal data were correlated with liver inflammation. Longitudinal data were obtained during treatment and correlated with virologic response. RESULTS: CCR5/CXCR3 expressing CD8+ cells were enriched in the liver and correlated with inflammation. Chronic HCV patients presented the same frequency of CCR5(high)/CXCR3(high) expressing CD8+ cells in peripheral blood as in healthy controls but higher serum concentration of CXCL10/CCL3. Treatment with PEG-interferon alpha-2b plus ribavirin increased CCR5(high)/CXCR3(high) expressing CD8+ cells frequency in peripheral blood and decreased CXCL10/CCL3 serum concentration. Increase in CXCR3(high) expressing CD8+ cells after 24 weeks of treatment was correlated with SVR. CONCLUSIONS: In chronic hepatitis C, anti-viral treatment induces an increase in CD8+ cells expressing chemokine receptors associated with Tc1 response and a reduction in their ligands. Achievement of viral control is associated with an increase in CXCR3(high) expressing CD8+ cells during treatment.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Hepacivirus/immunology , Hepatitis C/immunology , Hepatitis C/virology , Receptors, CCR5/immunology , Receptors, CXCR3/immunology , Adult , Cell Death/drug effects , Cell Death/immunology , Chemokine CCL3/blood , Chemokine CCL3/immunology , Chemokine CXCL10/blood , Chemokine CXCL10/immunology , Chronic Disease/therapy , Cytokines/immunology , Cytokines/metabolism , Female , Genotype , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Humans , Interferon-alpha/pharmacology , Interferon-alpha/therapeutic use , Liver/immunology , Liver/physiopathology , Liver/virology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Middle Aged , Receptors, CCR5/blood , Receptors, CXCR3/blood , T-Lymphocytes, Cytotoxic/immunology , Up-Regulation/drug effects , Up-Regulation/immunology
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