Holger M Reichardt

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany

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Publications (105)648.2 Total impact

  • Nature 05/2015; 521(7552):E1-4. DOI:10.1038/nature14444 · 41.46 Impact Factor
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    ABSTRACT: The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll-like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR-induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti-inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN-sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions.GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 03/2015; 63(6). DOI:10.1002/glia.22803 · 6.03 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (ko) mice and conditional ko mice lacking BDNF specifically in this lymphoid subset. In both settings, we observed diminished T-cell cellularity in peripheral lymphoid organs and an increase in CD4(+) CD44(+) memory T cells. Analysis of thymocyte development revealed diminished total thymocyte numbers, accompanied by a significant increase in CD4/CD8 double negative (DN) thymocytes due to a partial block in the transition from the DN3 to the DN4 stage. This was neither due to increased thymocyte apoptosis nor defects in the expression of the TCR β-chain or the pre-TCR. In contrast, pERK but not pAKT levels were diminished in DN3 BDNF-deficient thymocytes. BDNF deficiency in T cells did not result in gross deficits in peripheral acute immune responses nor in changes of the homeostatic proliferation of peripheral T cells. Taken together, our data reveal a critical autocrine and/or paracrine role of T-cell-derived BDNF in thymocyte maturation involving ERK-mediated TCR signalling pathways. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 01/2015; 45(5). DOI:10.1002/eji.201444985 · 4.03 Impact Factor
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    ABSTRACT: Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT). Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16(INK4A) expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression. Positivity for HPV DNA (44 samples, 18.9 %) and p16(INK4A) expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16(INK4A) expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16(INK4A) expression and HGAOT, patients with HGAOT only, patients with p16(INK4A) expression only, and patients without p16(INK4A) expression or HGAOT, respectively. After multivariate testing p16(INK4A) expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS. P16(INK4A) expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16(INK4A) expression is particularly important for patients without HGAOT.
    Strahlentherapie und Onkologie 01/2015; 191(7). DOI:10.1007/s00066-014-0801-3 · 2.91 Impact Factor
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    ABSTRACT: Glucocorticoids (GCs) are released from the adrenal gland during inflammation and help to keep immune responses at bay. Owing to their potent anti-inflammatory activity GCs also play a key role in controlling acute graft-versus-host disease (aGvHD). Here we demonstrate that mice lacking the glucocorticoid receptor (GR) in T cells develop fulminant disease after allogeneic bone marrow transplantation. In a fully MHC-mismatched model, transfer of GR-deficient T cells resulted in severe aGvHD symptoms and strongly decreased survival times. Histopathological features were aggravated and infiltration of CD8+ T cells into the jejunum was increased when the GR was not expressed. Furthermore, serum levels of IL-2, IFNγ and IL-17 were elevated and the cytotoxicity of CD8+ T cells enhanced after transfer of GR-deficient T cells. Short-term treatment with dexamethasone reduced cytokine secretion but neither impacted disease severity nor the CTLs’ cytolytic capacity. Importantly, in an aGvHD model in which disease development exclusively depends on the presence of CD8+ T cells in the transplant, transfer of GR-deficient T cells aggravated clinical symptoms and reduced survival times as well. Taken together, our findings highlight that suppression of CD8+ T cell function is a crucial mechanism in the control of aGvHD by endogenous GCs.
    The Journal of Pathology 10/2014; 235(4). DOI:10.1002/path.4475 · 7.43 Impact Factor
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    ABSTRACT: Introduction: The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration upon Epo stimulation.Results: High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR positive cells in the adult heart were identified in a CPC-enriched cell population and showed co-expression of stem, mesenchymal, endothelial and cardiomyogenic cell markers. We focused on the population co-expressing early (TBX5, NKX2.5) and definitive (myosin heavy chain (MHC), cardiac Troponin T (cTNT)) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Epo-responsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated towards cardiomyocyte-like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase of cardiac EMCs and cTNT positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function as compared to control mice.Conclusion: Our study characterized an EPO-responsive MHC-expressing cell population in the adult heart. Repetitive, moderate-dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post-ischemic cardiac function. Stem Cells 2014
    Stem Cells 09/2014; 32(9). DOI:10.1002/stem.1741 · 6.52 Impact Factor
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    ABSTRACT: Background Graft-versus-host disease (GvHD) is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP) is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles. Methods We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup. Results We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor’s genetic background we could not observe a statistically significant therapeutic effect. Conclusions Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor’s genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation.
    PLoS ONE 08/2014; 9(8):e105896. DOI:10.1371/journal.pone.0105896 · 3.23 Impact Factor
  • Holger M Reichardt · Henrike J Fischer
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    ABSTRACT: Transgenesis is a valuable tool with which to study different aspects of gene function in the context of the intact organism. During the last two decades a tremendous number of transgenic animals have been generated, and the continuous improvement of technology and the development of new systems have fostered their widespread application in biomedical research. Generally, transgenic animals are generated by introducing foreign DNA into fertilized oocytes, which can be achieved either by injecting recombinant DNA into the pronucleus or by transferring lentiviral particles into the perivitelline space. While mice remain the favored species in many laboratories, there are a number of applications where the use of rats is advantageous. One such research area is multiple sclerosis. Here, several experimental models are available that are closely mimicking the human disease, and it is possible to induce neuroinflammation by transferring pathogenic T cells which can then be studied by flow cytometry and 2-photon live imaging. Unlike for mice, the development of transgenic rats has encountered some hurdles in the past, e.g., due to a complicated reproductive biology and the frailty of the fertilized oocytes in vitro. In this chapter we provide a protocol describing how we manipulate single cell embryos in our lab in order to efficiently generate transgenic rats in a variety of different strains using lentiviral gene transfer.
    Methods in Molecular Biology 07/2014; 1304. DOI:10.1007/7651_2014_107 · 1.29 Impact Factor
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    ABSTRACT: Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis, and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR). Gastroparesis was unrelated to the enhanced gastric acid secretion observed after Dex treatment although both effects were mediated by the same molecular mechanism of the GR. Using conditional GR knock-out mice we could further rule out that GC effects on enterocytes or myeloid cells were involved in the induction of gastroparesis. In contrast, we found that Dex up-regulated arginase 2 (Arg2) in the stomach both at the mRNA and protein level. This suggests that GC treatment leads to a depletion of L-arginine thereby impeding the production of nitric oxide (NO) which is required for gastric motility. We tested this hypothesis by supplementing the drinking water of the mice with exogenous L-arginine to compensate for the presumed shortage of this major substrate of NO synthases. Importantly, this measure completely prevented both the enlargement of the stomach and the induction of gastroparesis after Dex treatment. Our findings raise considerations of combining orally applied GCs with L-arginine to improve tolerability of GC treatment and provide a possible explanation for the anti-emetic effects of GCs widely exploited in chemotherapy.
    Endocrinology 07/2014; 155(10):en20141246. DOI:10.1210/en.2014-1246 · 4.50 Impact Factor
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    ABSTRACT: Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.
    PLoS ONE 04/2014; 9(4):e93555. DOI:10.1371/journal.pone.0093555 · 3.23 Impact Factor
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    ABSTRACT: Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor(®) strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS.
    Acta Neuropathologica 02/2014; 127(5). DOI:10.1007/s00401-014-1248-4 · 10.76 Impact Factor
  • Marco J Herold · Holger M Reichardt
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    ABSTRACT: Glucocorticoids (GCs) are highly potent anti-inflammatory and immunosuppressive agents. They exert influence on many cell types of the immune system and impact a plethora of processes such as cytokine production, leukocyte differentiation, migration and adhesion, apoptosis induction, and changes in morphology. Those that are most relevant for the modulation of neuroinflammatory diseases, however, are still under debate. In this review, we will elaborate on how GCs impact inflammatory responses in general and revisit the ambivalent role that apoptosis plays in animal models of multiple sclerosis. Furthermore, we will discuss arguments that speak in favor or against an essential function of GC-induced apoptosis in neuroinflammation. We anticipate that a better knowledge of the mechanisms that GCs employ will eventually find its way into clinical practice for the future benefit of afflicted patients.
    Critical Reviews in Immunology 06/2013; 33(3):183-202. DOI:10.1615/CritRevImmunol.2013007415 · 3.70 Impact Factor
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    ABSTRACT: The role of CD8(+) T cells in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is still unclear. We describe here significantly reduced disease activity of EAE both in Lewis rats depleted of CD8(+) T cells by monoclonal antibodies and CD8 knockout rats, which was accompanied by reduced leukocyte infiltration into the spinal cord. We detected myelin basic protein (MBP)-specific CD4(+) T cells in peripheral lymphoid organs of CD8-depleted animals which, however, failed to differentiate into interferon-γ-producing effector cells. Our results indicate that CD8(+) T cells interact with myelin-specific CD4(+) T cells early in EAE enabling them to differentiate into pathogenic effector cells.
    Journal of neuroimmunology 05/2013; 260(1). DOI:10.1016/j.jneuroim.2013.04.014 · 2.47 Impact Factor
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    ABSTRACT: Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluorescently labeled nuclear factor of activated T cells (NFAT) with histone protein H2B to create a broadly applicable molecular sensor for intravital imaging of T cell activation. In experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, we report that effector T cells entering the CNS become activated after short contacts with leptomeningeal phagocytes. During established disease, the activation process is extended to the depth of the CNS parenchyma, where the cells form contacts with microglia and recruited phagocytes. We show that it is the activation processes during the preclinical phase rather than during established disease that are essential for the intensity and duration of the disease bout.
    Nature medicine 04/2013; 19(6). DOI:10.1038/nm.3182 · 27.36 Impact Factor
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    Henrike J Fischer · Nils Schweingruber · Fred Lühder · Holger M Reichardt
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    ABSTRACT: Glucocorticoids (GCs) are the most commonly prescribed drugs for the treatment of acute disease bouts in multiple sclerosis (MS) patients. While T lymphocytes were shown to be essential targets of GC therapy, at least in animal models of MS, the mechanisms by which GCs modulate T cell function are less clear. Until now, apoptosis induction and repression of pro-inflammatory cytokines in T cells have been considered the most critical mechanisms in ameliorating disease symptoms. However, this notion is being challenged by increasing evidence that the control of T cell migration and chemotaxis by GCs might be even more important for the treatment of neuroinflammatory diseases. In this review we aim to provide an overview of how GCs impact the morphological alterations that T cells undergo during activation and migration as well as the influences that GCs have on the directed movement of T cells under the influence of chemokines. A deeper understanding of these processes should not only help to advance our understanding of how GCs exert their beneficial effects in MS therapy but may reveal future strategies to intervene in the pathogenesis of neuroinflammatory diseases.
    Molecular and Cellular Endocrinology 04/2013; 380(1-2). DOI:10.1016/j.mce.2013.04.001 · 4.41 Impact Factor
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    ABSTRACT: Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFNγ secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and Treg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or γ-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.
    PLoS ONE 04/2013; 8(4):e61034. DOI:10.1371/journal.pone.0061034 · 3.23 Impact Factor
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    ABSTRACT: Glucocorticoids (GCs) repress lymphocyte function by controlling gene expression. In this study, we investigated Ag-specific effector T cells and provide evidence that GCs also modulate these cells' cytoskeletal architecture by nongenomic mechanisms. Following GC treatment, effector T cells rapidly lose their polarized morphology, which impedes both their migratory capacity and their interaction with APCs. The cytoskeleton rearrangements are preceded by an activation of ezrin-radixin-moesin proteins, which transiently increases the cellular rigidity but seems to occur independently of altered tyrosine phosphorylation. Phospholipase C activity is critically involved in mediating these nongenomic effects, because its inhibition prevents both T cell depolarization and ezrin-radixin-moesin phosphorylation after GC exposure. GC administration in vivo induced similar morphological changes in effector T cells as observed in vitro, suggesting that the above process plays a role in modulating inflammatory diseases. Taken together, our findings identify a novel mechanism through which GCs rapidly repress T cell function independently of gene transcription.
    The Journal of Immunology 03/2013; 190(8). DOI:10.4049/jimmunol.1201520 · 4.92 Impact Factor
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    Simone Wüst · Jens van den Brandt · Holger M Reichardt · Fred Lühder
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    ABSTRACT: Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leukocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy.
    International Journal of Endocrinology 11/2012; 2012:417017. DOI:10.1155/2012/417017 · 1.95 Impact Factor

Publication Stats

6k Citations
648.20 Total Impact Points


  • 2007–2015
    • Georg-August-Universität Göttingen
      • • Institute for Cellular and Molecular Immunology
      • • Göttingen Center for Molecular Biosciences (GZMB)
      • • Institute of Inorganic Chemistry
      Göttingen, Lower Saxony, Germany
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
  • 2014
    • Universitätsklinikum Freiburg
      • Institute of Human Genetics
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2008–2014
    • Universitätsmedizin Göttingen
      • Department of Cellular and Molecular Immunology
      Göttingen, Lower Saxony, Germany
  • 2013
    • The Walter and Eliza Hall Institute of Medical Research
      Melbourne, Victoria, Australia
  • 2004–2013
    • University of Wuerzburg
      • Institute for Virology and Immune Biology
      Würzburg, Bavaria, Germany
  • 2011
    • Leibniz Institute for Age Research - Fritz Lipmann Institute
      Jena, Thuringia, Germany
    • University of Cologne
      • Institute for Medical Microbiology, Immunology and Hygiene
      Köln, North Rhine-Westphalia, Germany
  • 2010
    • University of Greifswald
      • Department of Laboratory Animal Science
      Greifswald, Mecklenburg-Vorpommern, Germany
    • Technische Universität Hamburg-Harburg
      Hamburg, Hamburg, Germany
  • 2009
    • Benaroya Research Institute
      Seattle, Washington, United States
  • 1999–2002
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 1998–2002
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1996–2002
    • German Cancer Research Center
      • Division of Molecular Biology of the Cell II
      Heidelburg, Baden-Württemberg, Germany