• Budesonide in Autoimmune Hepatitis: The Right Drug at the Right Time for the Right Patient.

      Manns, Michael P; Jaeckel, Elmar; Taubert, Richard; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017-11-08)
    • Challenges in warranting access to prophylaxis and therapy for hepatitis B virus infection.

      Debarry, Jennifer; Cornberg, Markus; Manns, Michael P; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017-01)
      Despite an available vaccine and efficient treatment for hepatitis B virus (HBV) infection, chronic HBV infection still remains a major global threat, and one of the top 20 causes of human mortality worldwide. One of the major challenges in controlling HBV infection is the high number of undiagnosed chronic carriers and the lack of access to prophylaxis and treatment in several parts of the world. We discuss relevant barriers that need to be overcome to achieve global control of HBV infection and make eradication possible. Most important, vaccination must be scaled-up to lower the risk of vertical transmission and decrease the number of new infections, and comprehensive screening programs must be linked to care to obtain a better rate of diagnosis and treatment. This can probably only be achieved if sustainable funding is available. We therefore emphasize the importance of making the management of viral hepatitis a global health priority.
    • Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity.

      Strunz, Benedikt; Hengst, Julia; Deterding, Katja; Manns, Michael P; Cornberg, Markus; Ljunggren, Hans-Gustaf; Wedemeyer, Heiner; Björkström, Niklas K; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-06-11)
      Diversity is a central requirement for the immune system's capacity to adequately clear a variety of different infections. As such, natural killer (NK) cells represent a highly diverse population of innate lymphocytes important in the early response against viruses. Yet, the extent to which a chronic pathogen affects NK cell diversity is largely unknown. Here we study NK cell functional diversification in chronic hepatitis C virus (HCV) infection. High-dimensional flow cytometer assays combined with stochastic neighbor embedding analysis reveal that chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
    • DSA are associated with more graft injury, more fibrosis and upregulation of rejection associated transcripts in subclinical rejection.

      Höfer, Anne; Jonigk, Danny; Hartleben, Björn; Verboom, Murielle; Hallensleben, Michael; Hübscher, Stefan G; Manns, Michael P; Jaeckel, Elmar; Taubert, Richard; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Lippincott, Williams & Wilkins , 2019-10-23)
      Background: Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. Methods: To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance and immune regulation was analyzed in 77 biopsies with “no histological rejection” (NHR; n=25), “clinical TCMR” (cTMCR; n=16) and subTCMR (n=36). In addition, all available subTCMR biopsies (n=71) were tested for DSA with bead assays. Results: SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR.DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR associated transcripts. In nonsupervised analysis DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. Conclusion: T cell-mediated rejection seem to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
    • Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group.

      Than, Nwe Ni; Hodson, James; Schmidt-Martin, Daniel; Taubert, Richard; Wawman, Rebecca E; Botter, Meemee; Gautam, Nishant; Bock, Kilian; Jones, Rebecca; Appanna, Gautham D; et al. (Elsevier, 2019-12-01)
      Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded.
    • Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants.

      Khera, Tanvi; Behrendt, Patrick; Bankwitz, Dorothea; Brown, Richard J P; Todt, Daniel; Doepke, Mandy; Ghafoor Khan, Abdul; Schulze, Kai; Law, John; Logan, Michael; et al. (Elsevier, 2018-11-12)
      Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an HCV vaccine. Conserved epitopes like the viral CD81-binding site are targeted by rare broadly neutralizing antibodies. However, these viral segments are occluded by variable regions and glycans. We aimed to identify antigens exposing conserved epitopes and to characterize their immunogenicity. We created HCV variants with mutated glycosylation sites and/or hypervariable region 1 (HVR1). Exposure of the CD81 binding site and conserved epitopes was quantified by soluble CD81 and antibody interaction and neutralization assays. E2 or E1-E2 heterodimers with mutations causing epitope exposure were used to immunize mice. Vaccine-induced antibodies were examined and compared with patient-derived antibodies. Mutant viruses bound soluble CD81 and antibodies targeting the CD81 binding site with enhanced efficacy. Mice immunized with E2 or E1E2 heterodimers incorporating these modifications mounted strong, cross-binding, and non-interfering antibodies. E2-induced antibodies neutralized the autologous virus but they were not cross-neutralizing. Viruses lacking the HVR1 and selected glycosylation sites expose the CD81 binding site and cross-neutralization antibody epitopes. Recombinant E2 proteins carrying these modifications induce strong cross-binding but not cross-neutralizing antibodies.
    • Future Organization of Clinical Research in Germany: The Road to the "German Centre for Digestive Health" (GCDH).

      Manns, Michael P; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany. (2016-12)
    • Hepatitis D virus in Africa: several unmet needs.

      Manns, Michael P; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2017-10)
    • Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis.

      Tsay, Hsin-Chieh; Yuan, Qinggong; Balakrishnan, Asha; Kaiser, Marina; Möbus, Selina; Kozdrowska, Emilia; Farid, Marwa; Tegtmeyer, Pia-Katharina; Borst, Katharina; Vondran, Florian W R; et al. (Elsevier, 2018-12-22)
      Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive. Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis. Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.
    • MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis.

      Niehaus, Christian E; Strunz, Benedikt; Cornillet, Martin; Falk, Christine S; Schnieders, Ansgar; Maasoumy, Benjamin; Hardtke, Svenja; Manns, Michael P; Rm Kraft, Anke; Björkström, Niklas K; et al. (Wiley Online Open, 2020-02-03)
      Patients with advanced liver cirrhosis have an increased susceptibility to infections. As part of the cirrhosis-associated immune dysfunction, mucosal associated invariant T (MAIT) cells, that have the capacity to respond towards bacteria, are severely diminished in circulation and liver tissue. However, MAIT cell presence and function in the peritoneal cavity, a common anatomical site for infections in cirrhosis, remain elusive. To study this, matched peripheral blood and ascites fluid were collected from 35 patients with decompensated cirrhosis, with or without spontaneous bacterial peritonitis (SBP). MAIT cell phenotype and function were analyzed using high-dimensional flow cytometry and obtained data was compared to blood samples of healthy controls (n=24) and patients with compensated cirrhosis (n=11). We found circulating MAIT cells to be severely decreased in cirrhotic patients as compared to controls. In contrast, in ascites fluid, MAIT cells were significantly increased together with CD14+ CD16+ monocytes, ILCs, and NK cells. This was paralleled by elevated levels of several pro-inflammatory cytokines and chemokines in ascites fluid as compared to plasma. Peritoneal MAIT cells displayed an activated tissue-resident phenotype and this was corroborated by increased functional responses following stimulation with E. coli or lL-12 + IL-18 as compared to circulating MAIT cells. During SBP, peritoneal MAIT cell frequencies increased most among all major immune cell subsets, suggestive of active homing of MAIT cells to the site of infection. CONCLUSIONS: Despite severely diminished MAIT cell numbers and impaired phenotype in circulation, peritoneal MAIT cells remain abundant, activated, and highly functional in decompensated cirrhosis and are further enriched in SBP. This suggests that peritoneal MAIT cells could be of interest for immune intervention strategies in patients with decompensated liver cirrhosis and SBP.
    • Quantitation of large, middle and small hepatitis B surface proteins in HBeAg-positive patients treated with peginterferon alfa-2a.

      Rinker, Franziska; Bremer, Corinna M; Schröder, Kathrin; Wiegand, Steffen B; Bremer, Birgit; Manns, Michael P; Kraft, Anke R; Wedemeyer, Heiner; Yang, Lei; Pavlovic, Vedran; et al. (Wiley, 2019-11-13)
      BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive versus active chronic infection. Interferon alfa may convert HBeAg-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: HBs proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as hepatitis B e antigen (HBeAg) seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders versus nonresponders at all time points (P<.05) and decreased steadily during the initial 24 weeks' treatment (by 1.16 versus 0.86 ng/mL in responders/nonresponders, respectively) with unchanged relative proportions. Genotype B had a twofold higher proportion of LHBs than genotype C (13% versus 6%). HBV DNA, HBeAg, HBsAg, and HBs protein levels predicted response equally well but not optimally (area under the ROC curve values >0.70). CONCLUSIONS: HBs proteins levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.
    • Sonderforschungsbereich SFB 738: Optimierung konventioneller und innovativer Transplantate

      Manns, Michael P; Huber, Petra; Jaeckel, Elmar; Helmholtz Zentrum für Infektionsforschung GmbH, Inhoofenstr. 7, 38124 Braunschweig, Germany. (2017-08-09)