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1.
Artigo em Inglês | MEDLINE | ID: mdl-31373537

RESUMO

Treatment of chronic hepatitis B (CHB) typically requires life-long administration of drugs. Cohort and pre-clinical studies have established the link between a functional T-cell-mounted immunity and resolution of infection. TG1050 is an adenovirus 5- based vaccine that expresses HBV polymerase and domains of core and surface antigen and has shown immunogenicity and antiviral effects in mice. We performed a phase 1 clinical trial to assess safety and explore immunogenicity and early efficacy of TG1050 in CHB patients. This randomized, double blind, placebo-controlled study included 2 sequential phases: one single dose cohort (SD, n=12) and one multiple (3) doses cohort (MD, n= 36). Patients, virally suppressed under nucleoside(d)tide analog NUC therapy, were randomized 1:1:1 across 3 dose levels (DL) and assigned to receive 109, 1010, 1011 virus particles (vp) of TG1050 and then randomized within each DL to placebo (3:1 and 9:3 vaccines/placebo in each DL respectively for the SD and MD cohorts). Cellular (ELISPOT) and antibody responses (anti-Adenovirus) as well as evolution of circulating HBsAg and HBcrAg were monitored. All doses were well tolerated in both cohorts, without severe adverse event. TG1050 was capable to induce IFN-γ producing T-cells targeting 1 to 3 encoded antigens, in particular at the 1010vp dose. Overall, minor decreases of HBsAg were observed while a number of vaccinees reached unquantifiable HBcrAg by end of study. In CHB patients under NUC, TG1050 exhibited a good safety profile and was capable to induce HBV-specific cellular immune response. These data support further clinical evaluation, especially in combination studies.

2.
Nature ; 571(7764): 265-269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207605

RESUMO

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.

3.
J Hepatol ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173811

RESUMO

BACKGROUND & AIMS: CD100 is constitutively expressed on T cells and can be cleaved from the cell surface by matrix metalloproteases (MMPs) to become soluble CD100 (sCD100). Both membrane-bound CD100 (mCD100) and sCD100 have important immune regulatory functions that promote immune cell activation and responses. This study investigated the expression and role of mCD100 and sCD100 in regulating antiviral immune responses during HBV infection. METHODS: mCD100 expression on T cells, sCD100 levels in the serum, and MMP expression in the liver and serum were analysed in patients with chronic HBV (CHB) and in HBV-replicating mice. The ability of sCD100 to mediate antigen-presenting cell maturation, HBV-specific T cell activation, and HBV clearance were analysed in HBV-replicating mice and patients with CHB. RESULTS: Patients with CHB had higher mCD100 expression on T cells and lower serum sCD100 levels compared with healthy controls. Therapeutic sCD100 treatment resulted in the activation of DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses, and accelerated HBV clearance, whereas blockade of its receptor CD72 attenuated the intrahepatic anti-HBV CD8 T cell response. Together with MMP9, MMP2 mediated mCD100 shedding from the T cell surface. Patients with CHB had significantly lower serum MMP2 levels, which positively correlated with serum sCD100 levels, compared with healthy controls. Inhibition of MMP2/9 activity resulted in an attenuated anti-HBV T cell response and delayed HBV clearance in mice. CONCLUSIONS: MMP2/9-mediated sCD100 release has an important role in regulating intrahepatic anti-HBV CD8 T cell responses, thus mediating subsequent viral clearance during HBV infection. LAY SUMMARY: Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. The clearance of HBV relies largely on an effective T cell immune response, which usually becomes dysregulated in chronic HBV infection. Our study provides a new mechanism to elucidate HBV persistence and a new target for developing immunotherapy strategies in patients chronically infected with HBV.

4.
J Crohns Colitis ; 2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31051495

RESUMO

BACKGROUND AND AIMS: Dysregulated T cell responses contribute to the pathogenesis of inflammatory bowel disease (IBD). Since vitamin D (vitD) deficiency is a risk factor for adverse disease outcomes, we aimed to characterize the impact of vitD on intestinal and peripheral T cell profiles. METHODS: T cells were isolated from peripheral blood and intestinal biopsies of IBD patients, incubated with vitD and characterized by flow cytometry. To translate these in vitro findings to the clinic, serum vitD concentrations and clinical outcomes were correlated with T cell phenotype and function in a prospective patient cohort. RESULTS: Incubation of peripheral and intestinal T cells with 1,25(OH)2-vitD resulted in strongly reduced frequencies of pro-inflammatory CD4+ and CD8+ T cells producing IFNγ, IL-17, IL-22, IL-9 and TNF. Univariable analysis of 200 IBD patients revealed associations of vitD deficiency with incompliant vitD intake, season of the year and anemia in Crohn's disease (CD) as well as disease activity in ulcerative colitis (UC). Ex vivo immuno-phenotyping revealed that CD4+ and CD8+ T cell subsets were not substantially altered in vitD-deficient vs. -sufficient patients while regulatory T cell frequencies were reduced in UC and non-smoking CD patients with vitD deficiency. However, normalization of serum vitD concentrations in previously deficient CD patients resulted in significantly reduced frequencies of CD4+ T cells producing IFNγ, IL-17 and IL-22. CONCLUSION: VitD exerts profound anti-inflammatory effects on peripheral and intestinal CD4+ and CD8+ T cells of IBD patients in vitro and inhibits TH1 and TH17 cytokine production in CD patients in vivo.

5.
BMC Infect Dis ; 19(1): 395, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068145

RESUMO

BACKGROUND: Leptospirosis or Weil's disease is caused by pathogenic spirochete bacteria called Leptospira. It is considered the most common zoonosis in the world and is usually transmitted by urine of rodents and dogs with an incubation time of 7-14 days. The clinical spectrum ranges from a subclinical infection to a fulminant septic course. CASE PRESENTATION: Here, we report the case of a German patient with acute pancreatitis associated with Leptospira interrogans causing fulminant septic shock. The patient was successfully treated with intravenous antibiotics and left the hospital fully recovered after 18 days. CONCLUSIONS: To our knowledge, this is the first case of leptospirosis with acute pancreatitis as the leading clinical manifestation in Central Europe. Serologic and molecular genetic tests for leptospirosis should be considered, if no other causes for pancreatitis can be identified.


Assuntos
Leptospirose/complicações , Pancreatite/microbiologia , Choque Séptico/microbiologia , Vasoplegia/microbiologia , Idoso , Animais , Antibacterianos/uso terapêutico , Europa (Continente) , Humanos , Leptospira interrogans/patogenicidade , Leptospirose/tratamento farmacológico , Leptospirose/microbiologia , Masculino , Pancreatite/tratamento farmacológico , Pancreatite/etiologia , Choque Séptico/tratamento farmacológico , Choque Séptico/etiologia , Vasoplegia/tratamento farmacológico , Vasoplegia/etiologia , Zoonoses/tratamento farmacológico
6.
J Hepatol ; 71(3): 465-472, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31108159

RESUMO

BACKGROUND & AIMS: The burden of hepatitis E virus (HEV) infection among patients with haematological malignancy has only been scarcely reported. Therefore, we aimed to describe this burden in patients with haematological malignancies, including those receiving allogeneic haematopoietic stem cell transplantation. METHODS: We conducted a retrospective, multicentre cohort study across 11 European centres and collected clinical characteristics of 50 patients with haematological malignancy and RNA-positive, clinically overt hepatitis E between April 2014 and March 2017. The primary endpoint was HEV-associated mortality; the secondary endpoint was HEV-associated liver-related morbidity. RESULTS: The most frequent underlying haematological malignancies were aggressive non-Hodgkin lymphoma (NHL) (34%), indolent NHL (iNHL) (24%), and acute leukaemia (36%). Twenty-one (42%) patients had received allogeneic haematopoietic stem cell transplantation (alloHSCT). Death with ongoing hepatitis E occurred in 8 (16%) patients, including 1 patient with iNHL and 1 patient >100 days after alloHSCT in complete remission, and was associated with male sex (p = 0.040), cirrhosis (p = 0.006) and alloHSCT (p = 0.056). Blood-borne transmission of hepatitis E was demonstrated in 5 (10%) patients, and associated with liver-related mortality in 2 patients. Hepatitis E progressed to chronic hepatitis in 17 (34%) patients overall, and in 10 (47.6%) and 6 (50%) alloHSCT and iNHL patients, respectively. Hepatitis E was associated with acute or acute-on-chronic liver failure in 4 (8%) patients with 75% mortality. Ribavirin was administered to 24 (48%) patients, with an HEV clearance rate of 79.2%. Ribavirin treatment was associated with lower mortality (p = 0.037) and by trend with lower rates of chronicity (p = 0.407) when initiated <24 and <12 weeks after diagnosis of hepatitis E, respectively. Immunosuppressive treatment reductions were associated with mortality in 2 patients (28.6%). CONCLUSION: Hepatitis E is associated with mortality and liver-related morbidity in patients with haematological malignancy. Blood-borne transmission contributes to the burden. Ribavirin should be initiated early, whereas reduction of immunosuppressive treatment requires caution. LAY SUMMARY: Little is known about the burden of hepatitis E among patients with haematological malignancy. We conducted a retrospective European cohort study among 50 patients with haematological malignancy, including haematopoietic stem cell transplant recipients, with clinically significant HEV infection and found that hepatitis E is associated with hepatic and extrahepatic mortality, including among patients with indolent disease or among stem cell transplant recipients in complete remission. Hepatitis E virus infection evolved to chronic hepatitis in 5 (45.5%) patients exposed to a rituximab-containing regimen and 10 (47.6%) stem cell transplant recipients. Reducing immunosuppressive therapy because of hepatitis E was associated with mortality, while early ribavirin treatment was safe and effective.

7.
Lancet Gastroenterol Hepatol ; 4(7): 545-558, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30981686

RESUMO

Chronic hepatitis B virus (HBV) infection is a global public health challenge on the same scale as tuberculosis, HIV, and malaria. The International Coalition to Eliminate HBV (ICE-HBV) is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, we have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure. We believe that research must focus on the discovery of interventional strategies that will permanently reduce the number of productively infected cells or permanently silence the covalently closed circular DNA in those cells, and that will stimulate HBV-specific host immune responses which mimic spontaneous resolution of HBV infection. There is also a pressing need for the establishment of repositories of standardised HBV reagents and protocols that can be accessed by all HBV researchers throughout the world. The HBV cure research agenda outlined in this position paper will contribute markedly to the goal of eliminating HBV infection worldwide.

9.
Dtsch Med Wochenschr ; 144(8): 520-527, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30986859

RESUMO

Chronic viral hepatitis can remain unrecognized but may nevertheless lead to liver cirrhosis and hepatocellular carcinoma. Thus, patients with elevated liver enzymes as well as risk groups need to be screened and treated for viral hepatitis. These groups include, in particular, migrants from countries with high HBV or HCV prevalence, persons with previous or current intravenous drug use, and homosexual men. For HBV- or HCV-associated diseases, such as panarteriitis nodosa, cryoglobulinemic vasculitis or B-cell lymphoma, antiviral therapy may lead to remission. Prior to high-dose immunosuppressive therapy, especially with regimes containing rituximab, chronic or resolved HBV infection must be ruled out or antiviral prophylaxis may be required to avoid a potentially fatal HBV reactivation.


Assuntos
Hepatite Crônica/diagnóstico , Hepatite Viral Humana/diagnóstico , Doença Aguda , Hepatite Crônica/complicações , Hepatite Crônica/terapia , Hepatite Viral Humana/complicações , Hepatite Viral Humana/terapia , Humanos
10.
J Hepatol ; 70(6): 1103-1113, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30826436

RESUMO

BACKGROUND & AIMS: Current antiviral therapies lack the potential to eliminate persistent hepatitis B virus (HBV) infection. HBV-specific T cells are crucial for HBV control and have recently been shown to be protective in patients following discontinuation of antiviral therapy. Thus, T cell-based approaches may greatly improve the therapeutic landscape of HBV infection. We aimed to augment HBV-specific CD4 T cells from chronically infected patients by targeting different immunological pathways. METHODS: Expression of various co-stimulatory and inhibitory receptors on HBV- and influenza-specific CD4 T cells was analyzed directly ex vivo by MHC class II-tetramers. Patients infected with HBV genotype D were screened for CD4 T cell responses by IFN-γ ELISpot and intracellular cytokine staining following stimulation with overlapping peptides (OLPs) spanning the HBV-polyprotein. Stimulation with recombinant IL-7, an agonistic OX40-antibody or blockade of PD-L1 was performed in antigen-specific in vitro cultures. Cytokine secretion and expression of transcription factors were analyzed by flow cytometry. Responses targeting influenza, Epstein-Barr virus and tetanus toxoid served as controls. RESULTS: Tetramer-staining revealed that the IL-7 receptor-alpha (CD127), OX40 and PD-1 constitute possible therapeutic targets as they were all strongly expressed on HBV-specific CD4 T cells ex vivo. The HBV-specific CD4 T cell responses identified by OLP screening targeted predominantly the HBV-polymerase and core proteins. Combined OX40 stimulation and PD-L1 blockade significantly augmented IFN-γ and IL-21 producing HBV-specific CD4 T cells in vitro, suggesting active T helper type 1 cell and follicular T helper cell programs. Indeed, transcription factors T-bet and Bcl6 were strongly expressed in cytokine-producing cells. CONCLUSIONS: Combined OX40 stimulation and PD-L1 blockade augmented secretion of the helper T cell signature cytokines IFN-γ and IL-21, suggesting that immunotherapeutic approaches can improve HBV-specific CD4 T cell responses. LAY SUMMARY: CD4 T cells are important in controlling viral infections but are impaired in the context of chronic hepatitis B virus (HBV) infection. Therapeutic approaches to cure chronic HBV infection are highly likely to require an immune-stimulatory component. This study demonstrates that HBV-specific CD4 T cells can be functionally augmented by combined stimulation of the co-stimulatory molecule OX40 and blockade of the inhibitory PD-1 pathway.

11.
Dtsch Med Wochenschr ; 144(7): 489-493, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30925606

RESUMO

Scientifically active medical doctors are required for successful translation of novel basic findings into the clinic. However, there is an increasing tendency of young medical doctors to primarily follow a more clinically and not scientifically orientated career pathway. Therefore, the establishment of novel career education structures and career perspectives in university medicine are important to stop this development. Here, we will discuss the current situation and ongoing attempts to design novel structural programs that allow a better combination of clinical and scientific work by highlighting also current developments at the Faculty of Medicine at the University of Freiburg.


Assuntos
Escolha da Profissão , Medicina/organização & administração , Faculdades de Medicina , Universidades , Pesquisa Biomédica , Educação Médica , Humanos
12.
Viruses ; 11(2)2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813268

RESUMO

Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim⁻Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.


Assuntos
Artrite/virologia , Hepatite E/etiologia , Hepatite Crônica/etiologia , Adulto , Idoso , Antivirais/uso terapêutico , Artrite/complicações , Europa (Continente) , Feminino , Hepatite E/tratamento farmacológico , Hepatite Crônica/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Imunossupressão , Medicina Interna , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , RNA Viral , Recidiva , Estudos Retrospectivos , Reumatologia , Ribavirina/uso terapêutico , Fatores de Risco
13.
J Hepatol ; 70(6): 1072-1081, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30769005

RESUMO

BACKGROUND & AIMS: Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. METHODS: We performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury. RESULTS: Two hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV. CONCLUSIONS: ERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. LAY SUMMARY: Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.

14.
Cardiovasc Intervent Radiol ; 42(5): 729-736, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788517

RESUMO

Adjuvant embolization of varices may reduce rebleeding in patients with a transjugular intrahepatic portosystemic shunt (TIPS). The aim of this study was to investigate the efficacy and the risks of adjuvant variceal embolization at TIPS implantation using bucrylate. PATIENTS AND METHODS: The retrospective study evaluated 104 of 237 cirrhotic patients with TIPS for variceal bleeding who received adjuvant bucrylate embolization. For TIPS creation, bare stents were used in 35 patients (33.7%) and covered stents in 69 patients (66.3%) patients. Isolated gastric varices were seen in 10 patients (9.6%). RESULTS: Six patients (5.8%) rebled during a median follow-up time of 26 months (1-57 months). Rebleeding occurred in 14% (5/35) of patients with a bare stent but only in 1.4% (1/69) of patients with a covered stent. The 1- and 2-year rebleeding rates of all patients were 0.9 and 2.9% and of patients receiving a bare stent were 2.9 and 8.6%, respectively. Bucrylate migration was seen in 13 patients (12.5%). In 9 of these patients (8.7%), asymptomatic lung embolization occurred. This was rare in patients with esophageal varices (3.1%) but frequent (60%) in patients with isolated gastric varices and a spontaneous splenorenal shunt. CONCLUSIONS: Our results suggest that adjuvant embolization using bucrylate is effective and delays variceal rebleeding. The general use of covered stents, however, alleviates the utility of adjuvant bucrylate embolization which may be restricted to patients with a high risk of rebleeding indicated by large varices, active, acute or recent variceal bleeding and advanced cirrhosis. Bucrylate should not be used in isolated gastric varices because it bears a high risk of migration into the lungs.


Assuntos
Bucrilato/uso terapêutico , Embolização Terapêutica/métodos , Varizes Esofágicas e Gástricas/terapia , Cirrose Hepática/complicações , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Adesivos Teciduais/uso terapêutico , Terapia Combinada/métodos , Varizes Esofágicas e Gástricas/etiologia , Feminino , Seguimentos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
15.
Gastroenterology ; 156(6): 1820-1833, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30768983

RESUMO

BACKGROUND & AIMS: Hepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8+ T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8+ T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8+ T-cell-mediated response. METHODS: We collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and the Middle East, sequenced HDV, typed human leukocyte antigen (HLA) class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8+ T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection. RESULTS: We identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles (P < .005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8+ T cells; we confirmed that CD8+ T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8+ T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and they bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms. CONCLUSIONS: We analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8+ T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8+ T cells isolated from patients; these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Hepatite B Crônica/genética , Hepatite D Crônica/genética , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/imunologia , Vigilância Imunológica/imunologia , Superinfecção/genética , Alelos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Epitopos de Linfócito T/imunologia , Evolução Molecular , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Mutação , Polimorfismo Genético
16.
Cell Death Differ ; 26(9): 1688-1699, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30778201

RESUMO

Progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to non-alcoholic steatohepatitis (NASH) is a key step of NASH pathogenesis. The AP-1 transcription factor c-Jun is an important regulator of hepatic stress responses, but its contribution to NASH pathogenesis remains poorly defined. We therefore addressed c-Jun expression in liver biopsies of patients with steatosis and NASH. The role of c-Jun during NASH pathogenesis was analyzed mechanistically in c-Jun mutant mice fed with a methionine- and choline-deficient diet (MCDD). Disease progression from steatosis to NASH in patients correlated with increased c-Jun expression in hepatocytes, while its expression in non-parenchymal liver cells (NPLCs) particularly correlated with fibrosis. Analysis of untreated and MCDD-fed mice lacking c-Jun in hepatocytes (c-Jun∆li) revealed that c-Jun promotes hepatocyte survival, thereby protecting against the regenerative ductular reaction (DR) of Sox9/Osteopontin (Opn) co-expressing NPLCs, expression of the Opn receptor CD44 and fibrosis, which were all exacerbated in c-Jun∆li mice. Since Opn and c-Jun were co-expressed by NPLCs in mice and patients with NASH, we wondered whether the increased fibrosis observed in c-Jun∆li mice could be rescued by additional c-Jun deletion in NPLCs (c-Jun∆li*). c-Jun∆li* mice with NASH indeed exhibited reduced expression of Opn and CD44 in NPLCs, impaired DR and reduced fibrosis. A similar phenotype was observed in Opn knockout mice, suggesting that the observed functions of c-Jun were indeed Opn-dependent. In conclusion, c-Jun expression correlates with disease progression from steatosis to NASH in patients and exerts cell-type-specific functions in mice: In hepatocytes, it promotes cell survival thereby limiting the DR and fibrogenesis. In NPLCs, it rather promotes the DR and fibrogenesis by regulating expression of Opn and CD44.

17.
Hepatol Int ; 13(2): 113-124, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30600480

RESUMO

Chronic hepatitis B virus (HBV) infection is a major global health burden and cure is rarely achieved by current antiviral therapies. Therefore, there is an urgent need for new therapeutic options. Immune modulation with the goal to restore dysfunctional HBV-specific immunity is an interesting target for new therapeutic strategies. Based on the current evidence on immunology in resolving and persistent HBV infection, we will review the growing field of immunotherapeutic approaches for treatment of chronic HBV infection. We will also discuss the challenge of a heterogeneous patient population and personalized treatment as a possible key factor of success.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/terapia , Imunoterapia/métodos , Antivirais/uso terapêutico , Humanos , Imunidade Inata
18.
Gastrointest Endosc ; 89(6): 1180-1189.e1, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30653939

RESUMO

BACKGROUND AND AIMS: Current international guidelines recommend endoscopic resection for T1 colorectal cancer (CRC) with low-risk histology features and oncologic resection for those at high risk of lymphatic metastasis. Exact risk stratification is therefore crucial to avoid under-treatment as well as over-treatment. Endoscopic full-thickness resection (EFTR) has shown to be effective for treatment of non-lifting benign lesions. In this multicenter, retrospective study we aimed to evaluate efficacy, safety, and clinical value of EFTR for early CRC. METHODS: Records of 1234 patients undergoing EFTR for various indications at 96 centers were screened for eligibility. A total of 156 patients with histologic evidence of adenocarcinoma were identified. This cohort included 64 cases undergoing EFTR after incomplete resection of a malignant polyp (group 1) and 92 non-lifting lesions (group 2). Endpoints of the study were: technical success, R0-resection, adverse events, and successful discrimination of high-risk versus low-risk tumors. RESULTS: Technical success was achieved in 144 out of 156 (92.3%). Mean procedural time was 42 minutes. R0 resection was achieved in 112 of 156 (71.8%). Subgroup analysis showed a R0 resection rate of 87.5% in Group 1 and 60.9% in Group 2 (P < .001). Severe procedure-related adverse events were recorded in 3.9% of patients. Discrimination between high-risk versus low-risk tumor was successful in 155 of 156 cases (99.3%). In Group 1, 84.1% were identified as low-risk lesions, whereas 16.3% in group 2 had low-risk features. In total, 53 patients (34%) underwent oncologic resection due to high-risk features whereas 98 patients (62%) were followed endoscopically. CONCLUSIONS: In early colorectal cancer, EFTR is technically feasible and safe. It allows exact histological risk stratification and can avoid surgery for low-risk lesions. Prospective studies are required to further define indications for EFTR in malignant colorectal lesions and to evaluate long-term outcome.

19.
Gut ; 68(5): 905-915, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30622109

RESUMO

OBJECTIVE: A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. DESIGN: By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. RESULTS: HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. CONCLUSIONS: Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Produtos do Gene pol/metabolismo , Vírus da Hepatite B/imunologia , Hepatite B Crônica/metabolismo , Proteínas do Core Viral/metabolismo , Carga Viral , Adulto , Idoso , Estudos de Coortes , Feminino , Hepatite B Crônica/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
20.
Z Gastroenterol ; 57(1): 74-86, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30641606

RESUMO

The success of immune modulation by checkpoint blockade approaches is currently transforming oncology, with high and long-lasting tumor responses in patients with advanced disease across many cancer entities. Rooted in the reinvigoration of adaptive antitumor immune responses through disinhibition of negative feedback pathways, these approaches are particularly effective in patients with significant preexisting T cell responses in tumors with high neoantigen load. While promising data is starting to emerge from clinical trials in liver cancer patients, the underlying immunobiology remains poorly understood. In this review, we discuss the immunological mechanisms underlying the success of current checkpoint blockade therapies and the implications for hepatology including management of immune-related hepatitis. Checkpoint blockade therapy provides novel therapeutic options for difficult-to-treat liver cancers but also novel clinical challenges for hepatologists facing immune-related adverse events.

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