Christian Kurts

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (139)1219.82 Total impact

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    ABSTRACT: Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.
    Journal of the American Society of Nephrology : JASN. 06/2014;
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    ABSTRACT: In the liver, antigen-presenting cell populations such as Kupffer cells, liver dendritic cells and liver sinusoidal endothelial cells (LSECs) participate through cross-presentation to CD8 T cells (CTLs) in hepatic immune-regulation and immune-surveillance. The participation of hepatic stellate cells (HSCs) in immune regulation is controversial. Here we studied HSC's contribution to antiviral CTL immunity. Flow cytometric analysis of MHC-I molecules at the cell surface of liver cells from mice with cell-type restricted MHC-I expression. Mice with HSC-restricted MHC-I expression were infected with a hepatotropic virus and analyzed for development of viral hepatitis after CTL transfer. HSCs transferred MHC-I molecules to LSECs and these molecules were employed for LSEC cross-presentation to CTLs. Such transfer of MHC-I molecules was sufficient to support in vivo LSEC cross-presentation of soluble antigens to CTLs. Importantly, this transfer of MHC-I molecules contributed to anti-viral CTL immunity leading to development of immune-mediated hepatitis. Our findings demonstrate transfer of MHC-I molecules among sinusoidal liver cell populations as a potent mechanism to increase anti-viral CTL effector function. The transfer of MHC-I molecules from HSCs supplies LSECs with additional MHC-I molecules for their own cell-intrinsic cross-presentation. Such cross-allocation of MHC-I molecules in liver cell populations is distinct from cross-dressing that occurs among immune cell populations in lymphoid tissues where peptide-loaded MHC-I molecules are transferred. Our findings thus reveal a novel mechanism that increases local cross-presentation and CTL effector function in the liver, which may be instrumental for immune-surveillance during viral infection of antigen-presenting liver cells.
    Journal of Hepatology 05/2014; · 9.86 Impact Factor
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    ABSTRACT: The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.
    Cell 01/2014; 156(3):456-68. · 31.96 Impact Factor
  • Isis Ludwig-Portugall, Christian Kurts
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    ABSTRACT: The kidneys contain very few lymphocytes under homeostatic conditions. One kidney from a healthy mouse per average contains only 1-5 × 10(3) CD4(+) T cells. In immune-mediated kidney disease, γδ T cells, NKT cells, CD4(+) T cells, CD8(+) T cells, and regulatory T cells (Treg) infiltrate the kidney. Their numbers and subset composition of infiltrating T cells varies between the different forms of nephritis. For example, in glomerulonephritis CD4(+) T cells mediate renal injury, by local cytokine production, effector cell activation and/or by helping B cells to produce nephritogenic antibodies. A better understanding of the pathomechanisms of immune-mediated kidney diseases requires a method to isolate T cells from the kidney for ex vivo analysis. Here we describe an effective and specific isolation protocol for T cells from the murine kidney.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1193:27-35. · 1.29 Impact Factor
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    ABSTRACT: Age-related macular degeneration (AMD) is the most prevalent cause of blindness in the elderly, and its exsudative subtype critically depends on local production of vascular endothelial growth factor A (VEGF). Mononuclear phagocytes, such as macrophages and microglia cells, can produce VEGF. Their precursors, for example monocytes, can be recruited to sites of inflammation by the chemokine receptor CCR2, and this has been proposed to be important in AMD. To investigate the role of macrophages and CCR2 in AMD, we studied intracellular VEGF content in a laser-induced murine model of choroidal neovascularisation. To this end, we established a technique to quantify the VEGF content in cell subsets from the laser-treated retina and choroid separately. 3 days after laser, macrophage numbers and their VEGF content were substantially elevated in the choroid. Macrophage accumulation was CCR2-dependent, indicating recruitment from the circulation. In the retina, microglia cells were the main VEGF+ phagocyte type. A greater proportion of microglia cells contained VEGF after laser, and this was CCR2-independent. On day 6, VEGF-expressing macrophage numbers had already declined, whereas numbers of VEGF+ microglia cells remained increased. Other sources of VEGF detectable by flow cytometry included in dendritic cells and endothelial cells in both retina and choroid, and Müller cells/astrocytes in the retina. However, their VEGF content was not increased after laser. When we analyzed flatmounts of laser-treated eyes, CCR2-deficient mice showed reduced neovascular areas after 2 weeks, but this difference was not evident 3 weeks after laser. In summary, CCR2-dependent influx of macrophages causes a transient VEGF increase in the choroid. However, macrophages augmented choroidal neovascularization only initially, presumably because VEGF production by CCR2-independent eye cells prevailed at later time points. These findings identify macrophages as a relevant source of VEGF in laser-induced choroidal neovascularization but suggest that the therapeutic efficacy of CCR2-inhibition might be limited.
    PLoS ONE 01/2014; 9(4):e94313. · 3.73 Impact Factor
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    Christian Kurts
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    ABSTRACT: Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy.
    Kidney International 11/2013; 84(5):859-61. · 8.52 Impact Factor
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    ABSTRACT: The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α(-) CD11b(+) LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α(-) and CD8α(+) splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b(+) DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b(+) CCL17(+) DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 10/2013; · 4.97 Impact Factor
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    ABSTRACT: The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.
    Nature Reviews Immunology 09/2013; · 32.25 Impact Factor
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    ABSTRACT: DCs and macrophages both express the chemokine receptor CX3CR1. Here we demonstrate that its ligand, CX3CL1, is highly expressed in the murine kidney and intestine. CX3CR1 deficiency markedly reduced DC numbers in the healthy and inflamed kidney cortex, and to a lesser degree in the kidney medulla and intestine, but not in other organs. CX3CR1 also promoted influx of DC precursors in crescentic glomerulonephritis, a DC-dependent aggressive type of nephritis. Disease severity was strongly attenuated in CX3CR1-deficient mice. Primarily CX3CR1-dependent DCs in the kidney cortex processed antigen for the intrarenal stimulation of T helper cells, a function important for glomerulonephritis progression. In contrast, medullary DCs played a specialized role in inducing innate immunity against bacterial pyelonephritis by recruiting neutrophils through rapid chemokine production. CX3CR1 deficiency had little effect on the immune defense against pyelonephritis, as medullary DCs were less CX3CR1 dependent than cortical DCs and because recruited neutrophils produced chemokines to compensate for the DC paucity. These findings demonstrate that cortical and medullary DCs play specialized roles in their respective kidney compartments. We identify CX3CR1 as a potential therapeutic target in glomerulonephritis that may involve fewer adverse side effects, such as impaired anti-infectious defense or compromised DC functions in other organs.
    The Journal of clinical investigation 09/2013; · 15.39 Impact Factor
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    ABSTRACT: The JAK-inhibitor Ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anti-clonal activity. Here we investigated whether Ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final LPS-induced maturation step, Ruxolitinib reduced DC activation as demonstrated by decreased IL-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of Ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T cell responses. Ruxolitinib-treated mice immunized with OVA/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8(+) T cells compared to vehicle-treated controls. Finally, using an adenoviral infection model, we show that Ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that Ruxolitinib significantly affects DC differentiation and function leading to impaired T cell activation. DC dysfunction may result in increased infection rates in Ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK-inhibitors currently used in the treatment of MF and autoimmune diseases.
    Blood 06/2013; · 9.06 Impact Factor
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    ABSTRACT: BACKGROUND: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs. METHODS: We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14(+)HLA-DR(-/low) monocytes by flow cytometry, quantitative PCR and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14(+)HLA-DR(-/low) cells by using blocking antibodies or knock-down technology. RESULTS: Mature peripheral blood monocytes co-cultured with HSCs down-regulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14(+)HLA-DR(-/low) cells. Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. CONCLUSIONS: Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
    Journal of Hepatology 05/2013; · 9.86 Impact Factor
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    ABSTRACT: Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.
    Nature Immunology 04/2013; · 26.20 Impact Factor
  • André P Tittel, Christoph Heuser, Christian Kurts
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    ABSTRACT: This unit describes a simple way to induce pyelonephritis in female mice using uropathogenic Escherichia coli (UPEC). Methods for culturing and preparing working stocks of UPEC are provided. Protocols to measure the bacterial load in the murine kidney following the establishment of pyelonephritis by determining the bacterial colony forming units (CFU) are also included. This assay can be performed with kidney homogenates if the bacterial load is the sole read-out or if cellular intactness is not required for subsequent assays, or from kidney single cell suspensions prepared by enzymatic digestion. A support protocol describes methods for isolating cells for flow cytometry, ex vivo culture, and other assays. Curr. Protoc. Immunol. 101:15.23.1-15.23.9. © 2013 by John Wiley & Sons, Inc.
    Current protocols in immunology / edited by John E. Coligan ... [et al.] 04/2013; Chapter 15:Unit15.23.
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    ABSTRACT: Podocytes are essential to the structure and function of the glomerular filtration barrier; however, they also exhibit increased expression of MHC class II molecules under inflammatory conditions, and they remove Ig and immune complexes from the glomerular basement membrane (GBM). This finding suggests that podocytes may act as antigen-presenting cells, taking up and processing antigens to initiate specific T cell responses, similar to professional hematopoietic cells such as dendritic cells or macrophages. Here, MHC-antigen complexes expressed exclusively on podocytes of transgenic mice were sufficient to activate CD8+ T cells in vivo. In addition, deleting MHC class II exclusively on podocytes prevented the induction of experimental anti-GBM nephritis. Podocytes ingested soluble and particulate antigens, activated CD4+ T cells, and crosspresented exogenous antigen on MHC class I molecules to CD8+ T cells. In conclusion, podocytes participate in the antigen-specific activation of adaptive immune responses, providing a potential target for immunotherapies of inflammatory kidney diseases and transplant rejection.
    Journal of the American Society of Nephrology 03/2013; · 8.99 Impact Factor
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    ABSTRACT: Development of CD8(+) T cell (CTL) immunity or tolerance is linked to the conditions during T cell priming. Dendritic cells (DCs) matured during inflammation generate effector/memory T cells, whereas immature DCs cause T cell deletion/anergy. We identify a third outcome of T cell priming in absence of inflammation enabled by cross-presenting liver sinusoidal endothelial cells. Such priming generated memory T cells that were spared from deletion by immature DCs. Similar to central memory T cells, liver-primed T cells differentiated into effector CTLs upon antigen re-encounter on matured DCs even after prolonged absence of antigen. Their reactivation required combinatorial signaling through the TCR, CD28, and IL-12R and controlled bacterial and viral infections. Gene expression profiling identified liver-primed T cells as a distinct Neuropilin-1(+) memory population. Generation of liver-primed memory T cells may prevent pathogens that avoid DC maturation by innate immune escape from also escaping adaptive immunity through attrition of the T cell repertoire.
    Cell Reports 03/2013; · 7.20 Impact Factor
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    ABSTRACT: Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1) on cytotoxic T cells mediates to their tolerance. Renal lymph node DCs of the CD8(+) XCR1(+) subset, which depend on the transcription factor Batf3, expressed the PD-1 cognate ligand PD-L1. Batf3-dependent DCs in the renal lymph node presented antigen that had been concentrated in the kidney and used PD-L1 to induce apoptosis of cytotoxic T cells. In contrast, T cell tolerance in the spleen was independent of PD-1, PD-L1, and Batf3. In summary, these results clarify how the kidney/renal lymph node system tolerizes the immune system against circulating innocuous antigens.
    Journal of the American Society of Nephrology 02/2013; · 8.99 Impact Factor
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    ABSTRACT: Processing and presentation of antigen on MHC-I class I molecules serves to present peptides derived from cytosolic proteins to CD8(+) T cells. Infection with bacteria that remain in phagosomal compartments, such as Mycobacterium tuberculosis (Mtb), provides a challenge to this immune recognition as bacterial proteins are segregated from the cytosol. Previously we identified the Mtb phagosome itself as an organelle capable of loading MHC Class I molecules with Mtb antigens. Here, we find that the TAP transporter, responsible for importing peptides into the ER for loading in Class I molecules, is both present and functional in Mtb phagosomes. Furthermore, we describe a novel peptide reagent, representing the N-terminal domain of the bovine herpes virus UL49.5 protein, which is capable of specifically inhibiting the lumenal face of TAP. Together, these results provide insight into the mechanism by which peptides from intra-phagosomal pathogens are loaded onto Class I molecules.
    PLoS ONE 01/2013; 8(11):e79571. · 3.73 Impact Factor
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    Christian Kurts
    Frontiers in Immunology 01/2013; 4:51.
  • Lars Franken, Christian Kurts, Sven Burgdorf
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    ABSTRACT: Professional antigen-presenting cells such as dendritic cells (DCs) and macrophages internalize extracellular antigens, process them intracellularly, and present the resulting antigen-derived peptides in the context of MHC I or MHC II molecules. Since the intracellular routing of the antigen determines whether antigens are presented on MHC I or MHC II molecules, a profound analysis of the intracellular distribution of the internalized antigens is of high interest. Here, we describe an immunofluorescence protocol to monitor the intracellular routing of the model-antigen Ovalbumin in bone marrow-derived dendritic cells (BM-DCs). This protocol describes a procedure to stain such cells with antibodies against different endosomal markers, such as EEA1 and LAMP1, and can be easily adopted to other antigen-presenting cells or antigens.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 960:371-377. · 1.29 Impact Factor
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    ABSTRACT: Isolation and characterization of antigen-containing endosomes remains difficult utilizing standard purification techniques. Here, we describe a method, which allows isolation of antigen-loaded endosomes, that is based on flow cytometrical analysis and sorting. We specifically isolated antigen-containing endosomes from cells that had taken up fluorochrome-labeled ovalbumin via mannose receptor-mediated endocytosis. The protocol described here allows for the isolation of pure fractions of ovalbumin-containing endosomes and the extraction of proteins from these endosomes for analysis by western blot. Importantly, this protocol can be easily extended to other fluorochrome-labeled antigens and to primary antigen-presenting cells like bone marrow-derived dendritic cells.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 960:379-388. · 1.29 Impact Factor

Publication Stats

5k Citations
1,219.82 Total Impact Points

Institutions

  • 2005–2014
    • University of Bonn
      • • Institute of Experimental Immunology
      • • Institutes of Molecular Medicine and Experimental Immunology
      Bonn, North Rhine-Westphalia, Germany
  • 2012
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 2011
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
    • University Hospital München
      München, Bavaria, Germany
  • 2009
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
    • University of Wuerzburg
      • Institute for Virology and Immune Biology
      Würzburg, Bavaria, Germany
  • 2008–2009
    • University of Hamburg
      • Department of Internal Medicine II and Clinic (Oncology Center)
      Hamburg, Hamburg, Germany
  • 1998–2009
    • The Walter and Eliza Hall Institute of Medical Research
      • Division of Immunology
      Melbourne, Victoria, Australia
  • 2001–2008
    • RWTH Aachen University
      • • Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin (Medizinische Klinik I)
      • • Nephrology and Clinical Immunology (Internal Medicine II)
      Aachen, North Rhine-Westphalia, Germany
  • 2003–2007
    • University of Turku
      • MediCity Research Laboratory
      Turku, Western Finland, Finland
  • 1996–2007
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 1999
    • Hannover Medical School
      Hanover, Lower Saxony, Germany