Robert Thimme

Hôpital Fribourgeois, Freiburg, Fribourg, Switzerland

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Publications (227)1099.45 Total impact

  • Alimentary Pharmacology & Therapeutics 01/2015; 41(2). · 4.55 Impact Factor
  • Markus H. Heim, Robert Thimme
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    ABSTRACT: Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.
    Journal of Hepatology. 11/2014; 61(1).
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    ABSTRACT: Growing evidence suggests a role for the immunomodulatory cytokine interleukin-10 (IL-10) in hepatitis C virus (HCV)-specific CD8(+) T-cell failure. To address the possible role of IL-10 during priming, we performed in vitro priming experiments with naive HCV-specific CD8(+) T cells and autologous monocyte-derived dendritic cells in the absence or presence of IL-10. Our results showed that IL-10, when present during priming, significantly reduced the frequency of HCV-specific CD8(+) T cells after coculture; It was directly targeting CD8(+) T cells and led to impaired effector cell differentiation. These results may provide a possible mechanistic basis for the association between early IL-10 elevation, T-cell failure, and viral persistence.
    The Journal of infectious diseases. 10/2014;
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    ABSTRACT: Portal hypertension and hepatocellular carcinoma (HCC) are major complications of advanced liver cirrhosis. Thus, patients are often affected by both complications. Transjugular intrahepatic portosystemic shunt (TIPSS) is an effective treatment for portal hypertension and its complications. However, no established guidelines for the treatment of symptomatic portal hypertension in HCC patients are currently available. In addition, only limited information exists about the consequence of TIPSS implantation in patients with HCC.
    Alimentary Pharmacology & Therapeutics 10/2014; · 4.55 Impact Factor
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    ABSTRACT: The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
    Nature Medicine 10/2014; · 22.86 Impact Factor
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    ABSTRACT: Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically genotype 1a infected, HLA-A*02:01(+) patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector-memory phenotype whereas, surprisingly, one third displayed a naïve-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector-memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naïve-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naïve-like CD8(+) T cells from patients with consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.
    Journal of virology. 10/2014;
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    ABSTRACT: Skewed T helper (TH) cell responses and specific functions of TH1, TH2, TH17, and Treg cells have been implicated in the pathogenesis of inflammatory bowel disease (IBD) that led to the establishment of the pathogenic TH1/TH2 and TH17/Treg cell imbalance paradigms. However, the relevant TH cell population driving mucosal inflammation is still unknown.
    Inflammatory Bowel Diseases 09/2014; · 5.12 Impact Factor
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    ABSTRACT: The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
    The Journal of experimental medicine. 09/2014;
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    ABSTRACT: Acute graft-versus-host disease (GvHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT), therefore a better understanding of its biology may improve therapeutic options. We observed miR-146a upregulation in T cells of mice developing acute GvHD compared to untreated mice. Transplanting miR-146a(-/-) T cells caused increased GvHD severity, elevated TNF serum levels and reduced survival. TNF receptor-associated factor 6(TRAF6), a verified target of miR-146a, was upregulated in miR-146a(-/-) T cells following alloantigen stimulation. Higher TRAF6 levels translated into increased NF-κB activity and TNF production in miR-146a(-/-) T cells. Conversely, the detrimental effect of miR-146a deficiency in T cells was antagonized by TNF blockade, while phytochemical induction of miR-146a or its overexpression using a miR-146a mimic reduced GvHD severity. In humans, the minor genotype of the SNP rs2910164 in HCT donors, which reduces expression of miR-146a, was associated with severe acute GvHD (grade III/IV). We show that miR-146a functions as a negative regulator of donor T cells in GvHD by targeting TRAF6, leading to reduced TNF transcription. Since miR-146a expression can be exogenously enhanced, our results provide a novel, targeted molecular approach to mitigate GvHD.
    Blood 09/2014; · 9.78 Impact Factor
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    Annals of Hematology 07/2014; · 2.87 Impact Factor
  • Bertram Bengsch, Bianca Martin, Robert Thimme
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    ABSTRACT: The up-regulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T-cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T-cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T-cell failure and the impact of inhibitory receptor blockade on restoration of T-cell function in chronic HBV.
    Journal of Hepatology 07/2014; · 9.86 Impact Factor
  • Gut 06/2014; · 10.73 Impact Factor
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    ABSTRACT: Accumulation of CD3+TCRαβ+CD4-CD8- double negative T (DNT) cells is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory CD45RA+ (TEMRA) cells, but are CD27+CD28+KLRG1- and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4+ or CD8+ ALPS TEMRA cells. TCRβ deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4+ and CD8+TEMRA cells. Moreover, in ALPS patients with a germline FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas negative T-cells accumulated not only among DNT, but also among CD4+ and CD8+TEMRA cells. These data indicate that in human Fas deficiency DNT can not only derive from CD8+, but also from CD4+ T-cells. Furthermore, defective Fas signalling leads to aberrant transcriptional programs and differentiation of subsets of CD4+ and CD8+ T-cells. Accumulation of these cells before their double negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients.
    Blood 06/2014; · 9.78 Impact Factor
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection is characterized by a failure of virus-specific CD8+ T cells that is mainly caused by viral escape and T-cell exhaustion. Constant antigen stimulation has been suggested to contribute to HCV-specific CD8+ T-cell exhaustion. However, IFN-based therapies failed to recover HCV-specific CD8+ T-cell function suggesting that the damage to CD8+ T cells may be permanent even after antigen removal. It was therefore the objective of this study to analyze the impact of inhibition of ongoing viral replication by IFN-free therapy with direct acting antivirals (DAA) on the phenotype and function of HCV-specific CD8+ T cells.
    Journal of Hepatology 06/2014; · 9.86 Impact Factor
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    Euro surveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 05/2014; 19(21). · 5.49 Impact Factor
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    Percy A Knolle, Robert Thimme
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    ABSTRACT: The liver is an organ with unique immune regulatory functions favoring the induction of immune tolerance rather than immunity. These functions are mediated by local expression of co-inhibitory receptors and immunosuppressive mediators that help to prevent overwhelming tissue damage. Over the past years we have gained more insight into the local regulatory cues that determine the functional complexity of immune responses regulated locally within the liver. Both, the unique hepatic microenvironment and particular liver sinusoidal cell populations in addition to hepatocytes actively modulate immune responses locally in the liver and thereby determine the outcome of hepatic immune responses. This is of high biological and clinical relevance in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections that can cause acute and persistent infections associated with chronic inflammation in humans that eventually progress to liver cirrhosis and hepatocellular carcinoma (HCC). Here, we review current knowledge about the balance between immunity and tolerance in the liver and how this may impact our understanding of the determinants of HBV and HCV clearance, persistence and virus-induced liver disease.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24-72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002-1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975-0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000-1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073-2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271-4.695, P = 0.007) constituted the strongest predictors of treatment response. While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
    PLoS ONE 01/2014; 9(2):e87974. · 3.53 Impact Factor
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    Anita Schuch, Alexander Hoh, Robert Thimme
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    ABSTRACT: Hepatitis B virus (HBV) infection is one of the main causes of chronic liver diseases that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses are important factors that determine whether HBV infection is cleared or persists. Natural killer (NK) cells represent the main effector population of the innate immune system and are abundant in the human liver. Recently, it has been demonstrated that NK cells not only exhibit antiviral functions but may also regulate adaptive immune responses by deletion of HBV-specific CD8(+) T cells. It is well-established that HBV-specific CD8(+) T cells contribute to virus elimination. However, the mechanisms contributing to CD8(+) T cell failure in chronic HBV infection are not well-understood. In this review, we will summarize the current knowledge about NK cells and CD8(+) T cells and illustrate their contribution to viral clearance and persistence in HBV infection. Moreover, novel immunological in vitro model systems and techniques to analyze HBV-specific CD8(+) T cells, which are barely detectable using current multimer staining methods, will be discussed.
    Frontiers in Immunology 01/2014; 5:258.
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    ABSTRACT: The EASL Monothematic Conference on Translational Research in Viral Hepatitis brought together a group of leading scientists and clinicians working on both, basic and clinical aspects of viral hepatitis, thereby building bridges from bench to bedside. This report recapitulates the presentations and discussions at the conference held in Lyon, France on November 29-30, 2013. In recent years, great advances have been made in the field of viral hepatitis, particularly in hepatitis C virus (HCV) infection. The identification of IL28B genetic polymorphisms as a major determinant for spontaneous and treatment-induced HCV clearance was a seminal discovery. Currently, hepatologists are at the doorstep of even greater advances, with the advent of a wealth of directly acting antivirals (DAAs) against HCV. Indeed, promising results have accumulated over the last months and few years, showing sustained virological response (SVR) rates of up to 100% with interferon-free DAA combination therapies. Thus, less than 25 years after its identification, HCV infection may soon be curable in the vast majority of patients, highlighting the great success of HCV research over the last decades. However, viral hepatitis and its clinical complications such as liver cirrhosis and hepatocellular carcinoma (HCC) remain major global challenges. New therapeutic strategies to tackle hepatitis B virus (HBV) and hepatitis D virus (HDV) infection are needed, as current therapies have undeniable limitations. Nucleoside/nucleotide analogues (NUC) can efficiently control HBV replication and reduce or even reverse liver damage. However, these drugs have to be given for indefinite periods in most patients to maintain virological and biochemical responses. Although sustained responses off treatment can be achieved by treatment with (pegylated) interferon-α, only about 10-30% of patients effectively resolve chronic hepatitis B. It was the goal of this conference to review the progress made over the last years in chronic viral hepatitis research and to identify key questions that need to be addressed in order to close the gap between basic and clinical research and to develop novel preventive and treatment approaches for this most common cause of liver cirrhosis and HCC.
    Journal of Hepatology. 01/2014;

Publication Stats

5k Citations
1,099.45 Total Impact Points

Institutions

  • 2014
    • Hôpital Fribourgeois
      Freiburg, Fribourg, Switzerland
  • 1999–2014
    • Universitätsklinikum Freiburg
      • • Division of Infectious Diseases
      • • Department of Internal Medicine III
      • • Department of Internal Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1995–2014
    • University of Freiburg
      • • Faculty of Biology
      • • Department of Internal Medicine
      • • Department of Virology
      Freiburg, Baden-Württemberg, Germany
  • 2011
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2008–2011
    • University of Oxford
      • Nuffield Department of Clinical Medicine
      Oxford, ENG, United Kingdom
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 2009
    • Fundação Oswaldo Cruz
      • Departamento de Virologia (CPqAM)
      Rio de Janeiro, Rio de Janeiro, Brazil
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
    • Universität Heidelberg
      • Department of Molecular Virology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2007
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States
  • 2005
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
  • 2000–2004
    • The Scripps Research Institute
      • • Department of Molecular and Experimental Medicine
      • • Department of Chemistry
      La Jolla, CA, United States