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1.
Gut ; 73(10): 1737-1748, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39033025

RESUMO

OBJECTIVE: Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on. DESIGN: 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy. RESULTS: Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values. CONCLUSIONS: PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.


Assuntos
Antivirais , Antígenos E da Hepatite B , Hepatite B Crônica , Interferon-alfa , Células Matadoras Naturais , Polietilenoglicóis , Proteínas Recombinantes , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Hepatite B Crônica/sangue , Interferon-alfa/uso terapêutico , Antivirais/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Feminino , Adulto , Masculino , Polietilenoglicóis/uso terapêutico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Pessoa de Meia-Idade , Antígenos E da Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Quimioterapia Combinada , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento , Nucleosídeos/uso terapêutico
2.
Clin Liver Dis ; 27(4): 819-836, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37778772

RESUMO

The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.


Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Vírus da Hepatite B , Antígenos de Superfície da Hepatite B , Replicação Viral
3.
J Hepatol ; 74(4): 783-793, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33188902

RESUMO

BACKGROUND & AIMS: In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection. METHODS: Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds. RESULTS: HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade. CONCLUSIONS: Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection. LAY SUMMARY: In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepatite B Crônica , Compostos Fitoquímicos/farmacologia , Resveratrol/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Citocinas/biossíntese , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Humanos , Fatores Imunológicos , Glucosídeos Iridoides/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias Hepáticas/fisiologia , Polifenóis/farmacologia , Proteólise/efeitos dos fármacos , Deficiências na Proteostase
4.
Int J Infect Dis ; 62: 77-80, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28756023

RESUMO

OBJECTIVES: Cases of undiagnosed severe febrile rhabdomyolysis in refugees coming from West Africa, mainly from Nigeria, has been observed since May 2014. The aim of this study was to describe this phenomenon. METHODS: This was a multicentre retrospective observational study of cases of febrile rhabdomyolysis reported from May 2014 to December 2016 in 12 Italian centres. RESULTS: A total of 48 cases were observed, mainly in young males. The mean time interval between the day of departure from Libya and symptom onset was 26.2 days. An average 8.3 further days elapsed before medical care was sought. All patients were hospitalized with fever and very intense muscle aches. Creatine phosphokinase, aspartate aminotransferase, and lactate dehydrogenase values were abnormal in all cases. The rhabdomyolysis was ascribed to an infective agent in 16 (33.3%) cases. In the remaining cases, the aetiology was undefined. Four out of seven patients tested had sickle cell trait. No alcohol abuse or drug intake was reported, apart from a single reported case of khat ingestion. CONCLUSIONS: The long incubation period does not support a mechanical cause of rhabdomyolysis. Furthermore, viral infections such as those caused by coxsackievirus are rarely associated with such a severe clinical presentation. It is hypothesized that other predisposing conditions like genetic factors, unknown infections, or unreported non-conventional remedies may be involved. Targeted surveillance of rhabdomyolysis cases is warranted.


Assuntos
Refugiados , Rabdomiólise/diagnóstico , Adulto , África Ocidental , Aspartato Aminotransferases/metabolismo , Creatina Quinase/metabolismo , Feminino , Febre , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Nigéria , Estudos Retrospectivos , Rabdomiólise/etiologia , Adulto Jovem
5.
Future Microbiol ; 11(1): 23-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26674160

RESUMO

The genus Asaia has gained much interest lately owing to constant new species discoveries and its role as a potential opportunistic pathogen to humans. Here we describe a transient bacteremia due to Asaia lannensis in a patient with a psychiatric disorder (compulsive self-injection of different substances). Common phenotypic methods of identification failed to identify this organism, and only restriction fragment lenght polymorphism of PCR-amplified 16S rRNA gene allowed for proper identification. The isolate was highly resistant to most antibiotics. The paper also discusses the currently available medical literature, acknowledges the potential problems linked to the isolation of these strains and proposes an approach to species identification that can be applied in a clinical microbiology laboratory.


Assuntos
Acetobacteraceae/isolamento & purificação , Bacteriemia/diagnóstico , Infecções por Bactérias Gram-Negativas/diagnóstico , Transtornos Mentais/complicações , Acetobacteraceae/classificação , Acetobacteraceae/efeitos dos fármacos , Acetobacteraceae/genética , Adulto , Antibacterianos/farmacologia , Bacteriemia/microbiologia , Técnicas Bacteriológicas/métodos , DNA Bacteriano/genética , DNA Ribossômico/genética , Farmacorresistência Bacteriana Múltipla , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Polimorfismo de Fragmento de Restrição , RNA Ribossômico 16S/genética
6.
Gastroenterology ; 143(4): 963-73.e9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22796241

RESUMO

BACKGROUND & AIMS: In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. METHODS: We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS: Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS: In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Linfócitos T/metabolismo , Adenina/análogos & derivados , Adenina/uso terapêutico , Células Cultivadas , DNA Viral/sangue , Genótipo , Guanina/análogos & derivados , Guanina/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/sangue , Humanos , Interferon gama/metabolismo , Interleucina-1/metabolismo , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Tenofovir , Fator de Necrose Tumoral alfa/metabolismo
7.
J Hepatol ; 56(6): 1239-46, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22326467

RESUMO

BACKGROUND & AIMS: The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. METHODS: HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. RESULTS: Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. CONCLUSIONS: IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.


Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Linfócitos T/imunologia , Adulto , Idoso , Citocinas/biossíntese , Feminino , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/imunologia , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico
8.
J Immunother ; 31(3): 271-82, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18317360

RESUMO

Radiofrequency thermal ablation represents an effective treatment for hepatocellular carcinoma (HCC) and it can also exert an "adjuvant" effect on spontaneous antitumor T-cell responses, as suggested by human and animal studies. The adjuvant effect is thought to depend on the huge amount of necrotic tumor antigen made available to the immune system by HCC thermal ablation. In addition, radiofrequency thermal ablation may result in the release of local stimuli responsible for activation and maturation of antigen-presenting cells (APCs). To test this hypothesis, we studied APC maturation and function in 19 patients undergoing thermal ablation for HCC. Patients' monocytes induced to differentiate with granulocyte macrophage colony-stimulating factor (GM-CSF), or GM-CSF plus IL-4, were cocultured in vitro with tumor debris generated by radiofrequency thermal ablation. Expression of costimulatory molecules, lymphnode homing chemokine receptor, antigen presentation, and cytokine secretion were enhanced by incubation with HCC treated tissue as compared with untreated HCC and nontumor liver tissue. Moreover, HCC-specific T-cell responses could be induced by monocytes activated with GM-CSF and incubated with thermally ablated HCC tissue. HCC thermal ablation can create an antigenic source along with stimuli appropriate for maturation of APCs to induce HCC-specific T-cell responses. These results contribute to explain at least in part the adjuvant effect of HCC thermal ablation and suggest a novel strategy to induce maturation of APCs and their loading with HCC antigens for active immunotherapy protocols aimed at reducing HCC recurrence after thermal ablation.


Assuntos
Apresentação de Antígeno , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/imunologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Imunoterapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Extratos de Tecidos/imunologia , Regulação para Cima
9.
J Virol ; 80(22): 11398-403, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16956940

RESUMO

Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.


Assuntos
Antígenos CD/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Citometria de Fluxo , Humanos , Memória Imunológica , Subpopulações de Linfócitos , Receptor de Morte Celular Programada 1
10.
Cancer Res ; 66(2): 1139-46, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16424051

RESUMO

Radiofrequency thermal ablation (RFA) destroys tumoral tissue generating a local necrosis followed by marked inflammatory response with a dense T-cell infiltrate. In this study, we tested whether hepatocellular carcinoma thermal ablation can induce or enhance T-cell responses specific for hepatocellular carcinoma-associated antigens. Peripheral blood mononuclear cells derived from 20 patients with hepatocellular carcinoma were stimulated before and a month after RFA treatment with autologous hepatocellular carcinoma-derived protein lysates obtained before and immediately after RFA treatment. The effect of thermal ablation on memory T-cell responses to recall antigens [tetanus toxoid, protein purified derivative (PPD), Escherichia coli] was also assessed. T-cell reactivity was analyzed in an IFN-gamma enzyme-linked immunospot assay and by intracellular IFN-gamma staining. Treatment was followed by a significant increase of patients responsive either to tumor antigens derived from both the untreated hepatocellular carcinoma tissue (P < 0.05) and the necrotic tumor (P < 0.01) and by a higher frequency of circulating tumor-specific T cells. T-cell responses to recall antigens were also significantly augmented. Phenotypic analysis of circulating T and natural killer cells showed an increased expression of activation and cytotoxic surface markers. However, tumor-specific T-cell responses were not associated with protection from hepatocellular carcinoma relapse. Evidence of tumor immune escape was provided in one patient by the evidence that a new nodule of hepatocellular carcinoma recurrence was not recognized by T cells obtained at the time of RFA. In conclusion, RFA treatment generates the local conditions for activating the tumor-specific T-cell response. Although this effect is not sufficient for controlling hepatocellular carcinoma, it may represent the basis for the development of an adjuvant immunotherapy in patients undergoing RFA for primary and secondary liver tumors.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Linfócitos T/imunologia , Evasão Tumoral , Idoso , Antígenos de Neoplasias , Feminino , Humanos , Memória Imunológica , Inflamação , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Necrose , Recidiva Local de Neoplasia , Fenótipo
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