Robert Thimme

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (273)1450.54 Total impact

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    ABSTRACT: Virus-specific CD4(+) T cells play a major role in viral infections, such as hepatitis C virus (HCV). Viral clearance is associated with vigorous and multi-specific CD4(+) T-cell responses, while chronic infection has been shown to be associated with weak or absent T-cell responses. Most of these studies have used functional assays to analyze virus-specific CD4(+) T-cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4(+) T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analyzed in detail. A novel assay, in which virus-specific CD4(+) T-cell frequencies can be determined by de novo CD154 (CD40 ligand) expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4(+) T cells will be discussed in this review.
    Frontiers in Immunology 02/2015; 6:57. DOI:10.3389/fimmu.2015.00057
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    ABSTRACT: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described β2-microglobulin (β2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed. We sought to describe the molecular and immunologic features of β2m deficiency in 2 Turkish siblings with new diagnoses. Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry. Here we provide the first extensive clinical and immunologic description of β2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of β2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except β2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill." The clinical presentation of patients with β2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of β2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 02/2015; DOI:10.1016/j.jaci.2014.12.1937 · 11.25 Impact Factor
  • Christine Walker, Robert Thimme, Birke Bausch
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397232 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397223 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397248 · 1.67 Impact Factor
  • Gut 01/2015; DOI:10.1136/gutjnl-2014-308851 · 13.32 Impact Factor
  • Alimentary Pharmacology & Therapeutics 01/2015; 41(2). DOI:10.1111/apt.13038 · 4.55 Impact Factor
  • Michael Schultheiß, Robert Thimme
  • Katrin Busch, Robert Thimme
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    ABSTRACT: Hepatitis B virus infection represents a major global health problem. Currently, there are more than 240 million chronically infected people worldwide. The development of chronic hepatitis B virus-mediated liver disease may lead to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Recently, the discovery of the viral entry receptor sodium taurocholate cotransporting polypeptide has facilitated new approaches for a better understanding of viral physiopathology. Hopefully, these novel insights may give rise to the development of more effective antiviral therapy concepts during the next years. In this review, we will discuss the natural history of hepatitis B virus infection including the viral biology, the clinical course of infection and the role of the immune response.
    Medical Microbiology and Immunology 12/2014; 204(1). DOI:10.1007/s00430-014-0369-7 · 2.43 Impact Factor
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    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). DOI:10.1016/j.jhep.2014.06.035 · 10.40 Impact Factor
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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; 211(5). DOI:10.1093/infdis/jiu541 · 5.78 Impact Factor
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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; DOI:10.1111/apt.12994 · 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; DOI:10.1038/nm.3746 · 28.05 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 HCV genotype 1a-infected, HLA-A*02:01-positive 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 naive-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 naive-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, naive-like CD8+ T cells from patients with the 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. IMPORTANCE In this study, we analyzed CD8+ T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8+ T-cell populations in all patients. To further characterize these HCV-specific CD8+ T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8+ T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8+ T cells.
    Journal of Virology 10/2014; 89(1). DOI:10.1128/JVI.02242-14 · 4.65 Impact Factor
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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; DOI:10.1097/MIB.0000000000000210 · 5.48 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.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20131333 · 13.91 Impact Factor
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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; DOI:10.1182/blood-2014-04-569046 · 9.78 Impact Factor
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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 09/2014; DOI:10.1016/j.jhep.2014.05.016 · 10.40 Impact Factor

Publication Stats

7k Citations
1,450.54 Total Impact Points

Institutions

  • 1999–2015
    • Universitätsklinikum Freiburg
      • • Division of Infectious Diseases
      • • Department of Internal Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1995–2015
    • University of Freiburg
      • Faculty of Biology
      Freiburg, Baden-Württemberg, Germany
  • 2014
    • Hôpital Fribourgeois
      Freiburg, Fribourg, Switzerland
  • 2013–2014
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 2012
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2011
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2009
    • Fundação Oswaldo Cruz
      • Departamento de Virologia (CPqAM)
      Rio de Janeiro, Rio de Janeiro, Brazil
    • Universität Heidelberg
      • Department of Molecular Virology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2008
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 2007
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
    • 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