Marc Schmitz

Universität Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany

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Publications (118)478.53 Total impact

  • Haematologica 03/2014; · 5.94 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) are promising candidates for the treatment of graft-versus-host and autoimmune diseases. Here, by virtue of their immunosuppressive effects, they are discussed to exhibit inhibitory actions on various immune effector cells, including T lymphocytes that promote the underlying pathology. While it becomes apparent that MSCs exhibit their therapeutic effect in a transient manner, they are usually transplanted from third party donors into heavily immunocompromised patients. However, little is known about potential late complications of persisting third party MSCs in these patients. We therefore analysed the effect of gamma irradiation on the potency and proliferation of MSCs to elucidate an irradiation dose, which would allow inhibition of MSC proliferation while at the same time preserving their immunosuppressive function. Bone marrow-derived MSCs (BM-MSCs) were gamma-irradiated at increasing doses of 5, 10 and 30 Gy and subsequently assessed by colony formation unit (CFU)-assay, Annexin V-staining and in a mixed lymphocyte reaction, to assess colony growth, apoptosis and the immunosuppressive capacity, respectively. Complete loss of proliferative capacity measured by colony formation was observed after irradiation with a dose equal to or greater than 10 Gy. No significant decrease of viable cells was detected, as compared to non-irradiated BM-MSCs. Notably, irradiated BM-MSCs remained highly immunosuppressive in vitro for at least 5 days after irradiation. Gamma irradiation does not impair the immunosuppressive capacity of BM-MSCs in vitro and thus might increase the safety of MSC-based cell products in clinical applications.
    Journal of Cellular and Molecular Medicine 03/2014; · 4.75 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) play a crucial role in the development of cell-mediated immunotherapy due to their ability to induce and maintain strong immune responses. In our study, we evaluated a biocompatible Ni(II)-NTA-modified poly(ethylene imine) dendritic glycopolymer (Ni(II)-NTA-DG) as new carrier system to increase the antigen uptake into iDCs for future DC based immunotherapy. Ni(II)-NTA-DG led to an increase in His6-Gp160 uptake in monocytes and iDCs, where His6-Gp160 is localised in the early endosomal and lysosomal compartments. Ni(II)-NTA-DG and the formed polyplexes induced an activation of iDCs, showing an increasing expression of costimulatory molecules CD86, CD80 and proinflammatory cytokines IL-6 and IL-8. Beside no influencing effect of Ni(II)-NTA-DG and polyplexes on the maturation of antigen-bearing DCs, the mature peptide bearing DCs remained their ability to migrate along a gradient of CCR7 ligands. Thus, Ni(II)-NTA-DG with advancing biological properties is a promising carrier system for the future application in DC-based immunotherapy.
    Biomacromolecules 02/2014; · 5.37 Impact Factor
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    ABSTRACT: We have recently described a novel modular targeting platform for T cell recruitment that not only efficiently replaces but also is superior to conventional T cell-engaging bispecific antibodies as it allows for the flexible targeting of several antigens and the delivery of co-stimulatory ligands to malignant lesions, thereby enhancing the antitumor potential of redirected T cells.
    Oncoimmunology. 12/2013; 2(12):e26770.
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    ABSTRACT: Due to their clinical success there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform which consists of a universal effector and individual target modules. Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (e.g. the extracellular CD137 ligand domain) to the target module the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector to target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.Leukemia accepted article preview online, 20 August 2013. doi:10.1038/leu.2013.243.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2013; · 10.16 Impact Factor
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    ABSTRACT: The contribution of the bone marrow microenvironment in myelodysplastic syndrome is controversially discussed. Therefore, the functional properties of primary mesenchymal stromal cells from patients with myelodysplastic syndrome were analyzed in the presence or absence of lenalidomide. Compared to healthy controls, clonality and growth were reduced across all disease stages. Further, differentiation defects and particular expression of adhesion and cell surface molecules (e.g. CD166, CD29, CD146) were detected. Interestingly, the levels of stromal derived factor 1-alpha (SDF-1α) in patients' cells culture supernatants were almost 2-fold lower (p<0.01) compared to controls and this was paralleled by a reduced induction of migration of CD34+ hematopoietic cells. Cocultures of mesenchymal stromal cells from patients with CD34+ cells from healthy donors resulted in reduced numbers of cobblestone area forming-cells and fewer colony forming units. Exposure of stromal cells from patients and controls to lenalidomide led to a further reduction of SDF-1α secretion and cobblestone area formation, respectively. Moreover, lenalidomide pretreatment of mesenchymal stromal cells from low but not high-risk myelodysplastic syndrome was able to rescue impaired erythroid and myeloid colony formation of early hematopoietic progenitors. In conclusion, our analyses support the notion that the stromal microenvironment is involved in the pathophysiology of myelodysplastic syndrome thus representing a potential target for therapeutic interventions.
    Haematologica 05/2013; · 5.94 Impact Factor
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    ABSTRACT: Binding and uptake of immune complexes (ICs) via low-affinity Fc gamma receptors on dendritic cells (DCs) is well known as a booster of immune responses. It can be helpful when stimulating immunity against pathogenic microbes but may be harmful when antibodies form complexes with autologous antigens. No human DC subtype specialized in handling ICs has been identified to date. Incubating human blood mononuclear cells with ICs and studying their cellular binding, we identified 6-sulfo LacNAc-expressing DCs (slanDCs) as having an outstanding capacity to bind ICs compared to other myeloid DCs, plasmacytoid DCs or monocytes. Using selective blocking of different Fc gamma receptors, we identified CD16 (FcγRIII) as the major IC-binding structure on slanDCs. In addition, CD16 proved critical for phagocytosis of IgG-coated erythrocytes and CD16-targeted antigen led to a more efficient proliferation of CD4+ T cells than CD32 (FcγRII)-targeted antigen. Interestingly, these CD16-mediated functions are short lived and restricted to the immature stage of slanDCs in blood. We show that CD16 is rapidly shed from the surface of maturing slanDCs, resulting from the combined action of the metalloproteinases ADAM10 and ADAM17. In conclusion, these data provide strong evidence that slanDCs play an important role in IC-driven immune responses.
    Blood 03/2013; · 9.06 Impact Factor
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    ABSTRACT: Imiquimod and resiquimod represent Toll-like receptor (TLR) 7 and 8 agonists, which emerged as attractive candidates for tumor therapy. To elucidate immune cells, which mainly contribute to TLR7/8-mediated antitumoral activity, we investigated the impact of imiquimod and resiquimod on native human 6-sulfo LacNAc (slan) dendritic cells (DCs). We found that both TLR7/8 agonists significantly improve the release of various proinflammatory cytokines by slanDCs and promote their tumor-directed cytotoxic activity. Furthermore, resiquimod efficiently augmented the ability of slanDCs to stimulate T cells and natural killer cells. These results indicate that imiquimod and resiquimod trigger various immunostimulatory properties of slanDCs, which may contribute to their antitumor effects.
    Cancer letters 02/2013; · 4.86 Impact Factor
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    ABSTRACT: The nuclear autoantigen La can be detected on the surface of dying cells. Here we present an assay which enables us to show that La protein is not limited to the surface of dying cells but will be released upon stress-induced cell death. As released La protein tightly binds to the surface of neighboring intact cells we asked the question whether or not La protein could serve as a stress-inducible target e.g. for redirecting of regulatory T cells (Tregs) into damaged tissues to downregulate an immune response. In order to provide first proof of concept we developed a novel fully humanized single-chain bispecific antibody (bsAb) which on the one hand is directed to the La antigen and on the other hand to the CD3 complex of T cells. A cross-linkage of Tregs with La-decorated target cells mediated by this bsAb resulted indeed in the activation of the Tregs in a target-dependent manner. Moreover, such bsAb activated Tregs displayed a potent suppressive capacity and negatively influenced proliferation, expansion and cytokine production of autologous CD4(+) and CD8(+) Teff cells.
    Journal of Autoimmunity 01/2013; · 8.15 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2013; · 10.16 Impact Factor
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    ABSTRACT: Toll-like receptor (TLR) 3 agonists emerged as attractive candidates for vaccination strategies against tumors and pathogens. An important mechanism of action of such agonists is based on the activation of TLR3-expressing dendritic cells (DCs), which display a unique capacity to induce and stimulate T-cell responses. In this context, it has been demonstrated that targeting of TLR3 by double-stranded RNA such as poly(I:C) results in potent activation of DCs. Major disadvantages of poly(I:C) comprise its undefined chemical structure and very poor homogeneity, with subsequent unpredictable pharmacokinetics and high toxicity. In the present study, we evaluated the physicochemical properties and biological activity of the novel TLR3 agonist RGC100. RGC100 has a defined chemical structure, with a defined length (100 bp) and molecular weight (64.9 KDa) and a good solubility. RGC100 is stable in serum and activates myeloid DCs through TLR3 targeting, as evidenced by gene silencing experiments. Activation of mouse and human myeloid CD1c(+) DCs by RGC100 leads to secretion of several proinflammatory cytokines. In addition, RGC100 improves the ability of CD1c(+) DCs to stimulate T-cell proliferation. Due to its physicochemical properties and its immunostimulatory properties, RGC100 may represent a promising adjuvant for prophylactic and therapeutic vaccination strategies.
    Clinical and Developmental Immunology 01/2013; 2013:283649. · 3.06 Impact Factor
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    Blood Cancer Journal 01/2013; 3:e136. · 1.40 Impact Factor
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    ABSTRACT: Interleukin 17A (IL-17)-producing CD4(+) T helper type 17 (Th17) cells have recently drawn attention as possible effector cells of acute graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (HCT) in murine models. Their role following allogeneic HCT in humans is unknown. In this prospective study Th17, Th1/17 and Th1 cells were quantified in the peripheral blood of 80 patients within the first 3 months following allogeneic HCT using intracellular cytokine staining and flow cytometry. Within the observation period Th1, Th1/17 and Th17 cells did not reconstitute to levels of healthy controls. In contrast to Th1 cells, no further expansion of Th1/17 and Th17 cells was observed following the 1(st) month after HCT. ATG during conditioning significantly reduced the frequency of Th1/17 and Th17 cells, but not of Th1 cells. Acute GvHD was not associated with significant changes in the size of the Th1, Th1/17 or Th17 cell subsets. CMV reactivation triggered the expansion of all T helper subsets and Th1 cells showed the strongest increase. In contrast, no significant changes were found in the T helper cell compartment of patients with bacterial infections compared to time matched controls. In conclusion, quantitative reconstitution of Th1, Th1/17 and Th17 cells is impaired within the first 3 months after HCT, especially when ATG is administered during conditioning. CMV reactivation, but not acute GvHD or bacterial infection, triggered the absolute expansion of these T cell subsets.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2012; · 3.15 Impact Factor
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    ABSTRACT: Chemotherapy is an important treatment modality for many patients with advanced cancer. Recent data revealed that certain chemotherapeutic agents differentially affect maturation, cytokine production and T cell-stimulatory capacity of dendritic cells (DCs), which play a crucial role in the induction of antitumor immunity. Whereas most reports are based on mouse or human monocyte-derived DCs, studies investigating the direct effect of chemotherapeutic drugs on native human DCs are rather limited. Here, we evaluated the impact of various chemotherapeutic drugs on the immunostimulatory properties of 6-sulfo LacNAc(+) (slan) DCs, representing a major subpopulation of human blood DCs. Due to their various antitumor effects, slanDCs may essentially contribute to the immune defence against tumors. We demonstrated that doxorubicin and vinblastine significantly impair the release of TNF-α, IL-6, and IL-12 by slanDCs. Functional data revealed that both drugs inhibit slanDC-mediated proliferation of T lymphocytes and their capacity to differentiate naive CD4(+) T cells into proinflammatory T helper type I cells. Furthermore, these agents markedly suppressed the ability of slanDCs to stimulate interferon-γ secretion by natural killer (NK) cells. In contrast, paclitaxel, mitomycin C, and methotrexate sustained the ability of slanDCs to produce proinflammatory cytokines and their potential to activate T lymphocytes and NK cells. These results indicate that doxorubicin and vinblastine impair the ability of native human DCs to stimulate important immune effector cells, whereas methotrexate, mitomycin C, and paclitaxel maintain their immunostimulatory properties. These novel findings may have implications for the design of treatment modalities for tumor patients combining immunotherapeutic strategies and chemotherapy.
    International Journal of Cancer 08/2012; · 6.20 Impact Factor
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    ABSTRACT: Lupus erythematosus (LE) is an autoimmune disease with evidence for an IL-23- and IL-17-induced immunopathology. Little is known about the type of dendritic cells supporting this immune response. We recently demonstrated the strong Th1- and Th17-T-cell inducing capacity of human 6-sulfo LacNAc-dendritic cells (slanDCs), and identified slanDCs as inflammatory dermal dendritic cells in psoriasis locally expressing IL-23, TNF-α and inducible nitric oxide synthase (iNOS). In this study, we investigated the role of slanDCs in LE. Using immunohistochemistry, we identified slanDCs at increased frequency in affected skin lesions of cutaneous and systemic LE. slanDCs were found scattered in the dermal compartment and also clustered in lymph follicle-like structures. Here, they colocalized with T cells in the periphery but not with B cells in the center. The positive staining of dermal slanDCs for TNF-α indicated their pro-inflammatory status. In vitro the production of TNF-α was induced when slanDCs were cultured in the presence of serum from patients with LE. Stimulatory components of LE serum were previously identified as autoimmune complexes with ssRNA binding to TLR7 and TLR8. We found that slanDCs express mRNA for TLR7 and TLR8. slanDCs stimulated with ssRNA, selective TLR7 or TLR8 ligands responded with high-level TNF-α and IL-12 production. In contrast to slanDCs, the population of CD1c(+) DCs and plasmacytoid DCs (pDCs) expressed either TLR7 or TLR8, and their production of TNF-α and IL-12 to respective ligands was far less pronounced. We conclude that slanDCs have molecular and functional features of a pro-inflammatory myeloid DC type relevant for the immunopathogenesis of LE.
    Journal of Autoimmunity 08/2012; · 8.15 Impact Factor
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    ABSTRACT: Prostate cancer is the most common noncutaneous malignancy in men. The prostate stem cell Ag (PSCA) is a promising target for immunotherapy of advanced disease. Based on a novel mAb directed to PSCA, we established and compared a series of murine and humanized anti-CD3-anti-PSCA single-chain bispecific Abs. Their capability to redirect T cells for killing of tumor cells was analyzed. During these studies, we identified a novel bispecific humanized Ab that efficiently retargets T cells to tumor cells in a strictly Ag-dependent manner and at femtomolar concentrations. T cell activation, cytokine release, and lysis of target cells depend on a cross-linkage of redirected T cells with tumor cells, whereas binding of the anti-CD3 domain alone does not lead to an activation or cytokine release. Interestingly, both CD8(+) and CD4(+) T cells are activated in parallel and can efficiently mediate the lysis of tumor cells. However, the onset of killing via CD4(+) T cells is delayed. Furthermore, redirecting T cells via the novel humanized bispecific Abs results in a delay of tumor growth in xenografted nude mice.
    The Journal of Immunology 08/2012; 189(6):3249-59. · 5.52 Impact Factor
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    ABSTRACT: The concept that mesenchymal stromal cells (MSCs), a component of the hematopoietic microenvironment, can be a target for alloreactive effector cells in the context of graft-vs-host disease has not been investigated in detail. Mixed lymphocyte reaction (MLR) supernatant was used to mimic the inflammatory milieu induced by an allogeneic immune response in vitro. In addition to phenotype and proliferation, we monitored MSC differentiation, gene expression, and support of CD34(+) hematopoietic stem and progenitor cells after priming with MLR supernatant. Priming of MSCs with MLR supernatant led to an 11-fold decrease in cobblestone area-forming cells in the 4-week coculture (p < 0.05) and a threefold decrease of colony-forming unit macrophage in the colony-forming cell assay (p < 0.05). MSC proliferation over 8 days was increased 2.5-fold (p < 0.05). Osteogenic differentiation was enhanced, while adipogenesis was concurrently suppressed. In addition, the surface expression of HLA-DR and intercellular adhesion molecule-1 was increased 20-fold (p = 0.06) and 45-fold (p < 0.05), respectively. This was associated with increased adhesion of hematopoietic stem and progenitor cells to MLR-treated MSCs. In summary, our data shed light on the dysfunction of the stromal environment during graft-vs-host disease, possibly aggravating cytopenia and leading to an enhanced immunogenicity of MSCs.
    Experimental hematology 07/2012; 40(11):934-44. · 3.11 Impact Factor
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    ABSTRACT: Lenalidomide (LEN) has emerged as a promising therapeutic option for the management of various hematologic malignancies. Although its direct mechanisms of action on malignant cells have been studied intensively, its effects on the stromal compartment of bone marrow have not yet been analyzed systematically. Therefore, we investigated whether LEN alters the functional capacity of mesenchymal stromal cells (MSCs) as the main cellular component of the bone marrow microenvironment. In addition to their growth and differentiation characteristics, we focused on the ability of MSC to modulate T-cell function and support hematopoietic stem cells (HSCs). Bone marrow-derived MSCs were exposed to LEN (10 μM), and differences in proliferation, phenotype, inhibition of T-cell proliferation, and differentiation capacity were analyzed. A Boyden chamber assay was used to test the migratory potential of HSC toward the conditioned medium of LEN-treated or untreated MSCs, and the stromal cell-derived factor-1 (SDF-1) concentrations in these supernatants were determined by enzyme-linked immunosorbent assay. Treatment of MSCs with LEN did not affect their growth rate, proliferation, osteogenic and adipogenic differentiation potential, or capacity to inhibit T-cell proliferation. However, LEN treatment increased the average of mean fluorescence intensity of CD29 and CD73 by 15 and 22%, respectively. Interestingly, LEN reduced SDF-1 by MSCs by 32% compared to that of control cells. As a functional consequence, the serum-free supernatant of LEN-treated MSCs had a significantly lower potential to induce the directed migration of CD34(+) HSCs. LEN can modulate the expression of cell surface molecules and the chemokine secretion of MSCs in vitro. These effects might contribute to the clinical effects of the compound in vivo for patients with hematological malignancies.
    Experimental hematology 06/2012; 40(10):867-76. · 3.11 Impact Factor
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    ABSTRACT: BACKGROUND: Infections and acute graft-versus-host disease (GvHD) represent major complications of allogeneic stem-cell transplantation (SCT). Dendritic cells (DCs) display an extraordinary capacity to induce innate and adaptive immune responses. Therefore, they play a crucial role in the elimination of pathogens and in the pathogenesis of acute GvHD. 6-Sulfo LacNAc DCs (slanDCs) are a major subpopulation of human blood DCs with a high proinflammatory capacity. We investigated for the first time the reconstitution of slanDCs in the blood of patients after SCT and the modulation of their frequency by bacterial infection, cytomegalovirus (CMV) reactivation, and acute GvHD. METHODS: The frequency of slanDCs, CD1c myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) in the peripheral blood was quantified by flow cytometry in 80 patients after SCT. To assess individual DC subsets, we used pregating of the HLADRLin subset and antibodies against slanDCs, blood DC antigen 1 (CD1c mDCs), and blood DC antigen 2 (pDCs). RESULTS: SlanDCs showed the slowest reconstitution in the first month after SCT compared with CD1c mDCs and pDCs. Interestingly, in the second and third months after SCT, their percentage steadily increased, and slanDCs were the most abundant DC subset. In addition, we observed a markedly reduced frequency of slanDCs in the blood of patients with bacterial infection, CMV reactivation, or severe acute GvHD. Furthermore, slanDCs showed the most prominent reduction after steroid treatment of acute GvHD. CONCLUSIONS: These results indicate that SCT-associated complications such as bacterial infection, CMV reactivation, and acute GvHD can significantly modulate the frequency of slanDCs.
    Transplantation 05/2012; · 3.78 Impact Factor
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    ABSTRACT: Mesenchymal stromal cells (MSCs) have emerged as promising candidates for regenerative therapies, including tissue engineering. Recently it has been reported that engineered extracellular matrix (ECM) components support the differentiation of MSCs into osteocytes and chondrocytes, indicating that ECM components may represent attractive carriers for MSC transplants to repair damaged tissues. However, little is known about the impact of engineered ECM components on the immunosuppressive properties of MSCs, which may essentially contribute to the prevention of allogeneic MSC transplant rejection. In the present study, we explored the potential of fibronectin, fibrillar collagen I, tropocollagen and collagen I/heparin to influence the immunosuppressive capacities of MSCs. We found that these ECM components do not modulate the capability of MSCs to inhibit the proliferation of anti-CD3/anti-CD28 antibody-stimulated CD4(+) and CD8(+) T cells and of lymphocytes in a mixed lymphocyte reaction. In addition, the potential of MSCs to impair the production of immunostimulatory IL-12 and to improve the release of immunosuppressive IL-10 by 6-sulpho LacNAc(+) (slan) dendritic cells (DCs), representing a pro-inflammatory subset of human blood DCs, was not altered by the ECM components. Furthermore, ECM components do not influence the ability of MSCs to inhibit the slanDC-induced proliferation of CD4(+) T cells. In conclusion, the used engineered ECMs maintain important immunosuppressive properties of MSCs, which support their suitablility as carriers for MSC transplants in tissue engineering. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 05/2012; · 2.83 Impact Factor

Publication Stats

2k Citations
478.53 Total Impact Points

Institutions

  • 2012–2013
    • Universität Heidelberg
      • • Department of Dermatology
      • • University Hospital of Dermatology
      Heidelberg, Baden-Wuerttemberg, Germany
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
  • 2000–2013
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 1998–2013
    • Technische Universität Dresden
      • Institut für Immunologie
      Dresden, Saxony, Germany
  • 2003–2012
    • Universitätsklinikum Dresden
      • Medizinische Klinik I
      Dresden, Saxony, Germany
  • 1997–1998
    • Johannes Gutenberg-Universität Mainz
      • • I. Department of Medicine
      • • Institut für Physiologische Chemie
      Mainz, Rhineland-Palatinate, Germany