Marc Schmitz

Center for Regenerative Therapies, Dresden, Dresden, Saxony, Germany

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Publications (129)606.45 Total impact

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    ABSTRACT: Allogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCRα repertoire and its clinical relevance in patients following stem cell transplantation. Using next generation sequencing we examined the TCRα repertoire of CD8(+) T cells and CMV-specific CD8(+) T cells in four patients. Additionally, we performed single cell TCRαβ sequencing of CMV-specific CD8(+) T cells. The TCRα composition of (HLA)-A*0201 CMVpp65- and CMVIE-specific T cells was oligoclonal and defined by few dominant clonotypes. Frequencies of single clonotypes reached up to 11% of all CD8(+) T cells and half of the total CD8(+) T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCRα clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8(+) T cells was consistent with chronically activated effector memory T cells. The CD8(+) T cell response to CMV reactivation resulted in an expansion of a few TCRα clonotypes to dominate the CD8(+) repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective antiviral T cell response in this setting. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Clinical & Experimental Immunology
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    ABSTRACT: Acute graft-versus-host disease (aGvHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Steroid-resistant aGvHD is associated with poor outcome, and no commonly accepted salvage therapy is available for its treatment. Here, we report 58 adult patients treated with mesenchymal stromal cells (MSCs) as salvage therapy for steroid-refractory aGvHD. Third-party MSCs expanded in platelet lysate-containing medium were transfused at a median dose of 0.99 × 10(6) cells/kg bodyweight. A median of two MSC infusions were administered to each patient. Median time between the onset of aGvHD and the first infusion of MSCs was 12 days (range, 6-62 days). Most patients (79%) had grade IV aGvHD. Five patients showed complete response, five showed very good partial response, 17 showed partial response, and 31 showed no response. The estimated probability of survival after 1 year was 19%, and median survival was 69 days. Overall survival was not significantly different from that of a historical cohort of patients receiving alternative salvage therapy and no MSC infusions. In conclusion, MSC treatment on top of conventional immunosuppression was associated with an overall response rate of 47% but improved outcome in terms of survival remains to be shown. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Stem Cells
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    ABSTRACT: p38 Mitogen-activated protein kinase (MAPK) plays a crucial role in the induction and regulation of innate and adaptive immunity. Furthermore, p38 MAPK can promote tumor invasion, metastasis, and angiogenesis. Based on these properties, p38 MAPK inhibitors emerged as interesting candidates for the treatment of immune-mediated disorders and cancer. However, the majority of p38 MAPK inhibitor-based clinical trials failed due to poor efficacy or toxicity. Further studies investigating the influence of p38 MAPK inhibitors on immunomodulatory capabilities of human immune cells may improve their therapeutic potential. Here, we explored the impact of the p38 MAPK inhibitor SB203580 on the pro-inflammatory properties of native human 6-sulfo LacNAc dendritic cells (slanDCs). SB203580 did not modulate maturation of slanDCs and their capacity to promote T-cell proliferation. However, SB203580 significantly reduced the production of pro-inflammatory cytokines by activated slanDCs. Moreover, inhibition of p38 MAPK impaired the ability of slanDCs to differentiate naïve CD4(+) T cells into T helper 1 cells and to stimulate interferon-γ secretion by natural killer cells. These results provide evidence that SB203580 significantly inhibits various important immunostimulatory properties of slanDCs. This may have implications for the design of p38 MAPK inhibitor-based treatment strategies for immune-mediated disorders and cancer.
    No preview · Article · Sep 2015 · Immunobiology
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    ABSTRACT: Natural killer (NK) cells are promising effector cells for adjuvant immunotherapy of cancer. So far, several preclinical studies have shown the feasibility of gene-engineered NK cells, which upon expression of chimeric antigen receptors (CARs) are redirected to otherwise NK cell-resistant tumors. Yet, we reasoned that the efficiency of an immunotherapy using CAR-modified NK cells critically relies on efficient migration to the tumor site and might be improved by the engraftment of a receptor specific for a chemokine released by the tumor. On the basis of the DNAX-activation protein 12 (DAP12), a signaling adapter molecule involved in signal transduction of activating NK cell receptors, we constructed an epidermal growth factor variant III (EGFRvIII)-CAR, designated MR1.1-DAP12 which confers specific cytotoxicity of NK cell towards EGFRvIII glioblastoma cells in vitro and to established subcutaneous U87-MG tumor xenografts. So far, infusion of NK cells with expression of MR1.1-DAP12 caused a moderate but significantly delayed tumor growth and increased median survival time when compared with NK cells transduced with an ITAM-defective CAR. Notably, the further genetic engineering of these EGFRvIII-specific NK cells with the chemokine receptor CXCR4 conferred a specific chemotaxis to CXCL12/SDF-1α secreting U87-MG glioblastoma cells. Moreover, the administration of such NK cells resulted in complete tumor remission in a number of mice and a significantly increased survival when compared with the treatment of xenografts with NK cells expressing only the EGFRvIII-specific CAR or mock control. We conclude that chemokine receptor-engineered NK cells with concomitant expression of a tumor-specific CAR are a promising tool to improve adoptive tumor immunotherapy.
    Full-text · Article · Jun 2015 · Journal of immunotherapy (Hagerstown, Md.: 1997)
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    ABSTRACT: Recently, mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have been suggested as an alternative to MSCs for the treatment of various inflammatory disorders. However, while a first case report observed beneficial therapeutic effects of repeated MSC EV infusions in a patient with therapy refractory graft versus host disease (GvHD), in vitro findings revealed that MSC-EVs were significantly less immunosuppressive than their parental cells. Here, we compared the immunosuppressive potency of MSCs derived from bone marrow (BM-MSCs) and adipose tissue (AT MSCs), with their secreted EVs in a standardized lymphocyte proliferation assay (LPA). Both BM MSCs and AT-MSCs exhibited a remarkable inhibition of lymphocyte proliferation (LP) (88.1 ± 1.5% and 75.5 ± 1.5%, respectively), while isolated EVs derived from them failed to suppress LP at dose levels up to 100 µg/ml. Thus, our data further substantiate previous reports suggesting that cell-cell contact plays an important role on the immunosuppressive potential mediated by MSCs. Hence, MSC-EVs are still a matter of debate and might not be a reasonable substitute for MSCs with regard to the immunosuppressive function. Collectively, these contrasting findings may also reflect the importance of relevant translational aspects when designing new studies. Standardization of MSC culture conditions before EV collection, as well as isolation and characterization methods with regard to EV purity are urged. Moreover, prior to the clinical use, dose-finding studies evaluating MSC-EV preparations in suitable preclinical models are warranted.
    Full-text · Article · Mar 2015 · Stem Cells and Development
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    ABSTRACT: Dendritic cells (DCs) essentially contribute to the induction and regulation of innate and adaptive immunity. Based on these important properties, DCs may profoundly influence tumor progression in patients. However, little is known about the role of distinct human DC subsets in primary tumors and their impact on clinical outcome. In the present study, we investigated the characteristics of human 6-sulfo LacNAc (slan) DCs in clear cell renal cell carcinoma (ccRCC). slanDCs have been shown to display various tumor-directed properties and to accumulate in tumor-draining lymph nodes from patients. When evaluating 263 ccRCC and 227 tumor-free tissue samples, we found increased frequencies of slanDCs in ccRCC tissues compared to tumor-free tissues. slanDCs were also detectable in the majority of 24 metastatic lymph nodes and 67 distant metastases from ccRCC patients. Remarkably, a higher density of slanDCs was significantly associated with a reduced progression-free, tumor-specific or overall survival of ccRCC patients. Tumor-infiltrating slanDCs displayed an immature phenotype expressing interleukin-10. ccRCC cells efficiently impaired slanDC-induced T-cell proliferation and programming as well as natural killer (NK) cell activation. In conclusion, these findings indicate that higher slanDC numbers in ccRCC tissues are associated with poor prognosis. The induction of a tolerogenic phenotype in slanDCs leading to an insufficient activation of innate and adaptive antitumor immunity may represent a novel immune escape mechanism of ccRCC. These observations may have implications for the design of therapeutic strategies that harness tumor-directed functional properties of DCs against ccRCC.
    No preview · Article · Mar 2015 · OncoImmunology
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    ABSTRACT: Objective: To examine the potential role of 6-sulfo LacNAc(+) (slan) dendritic cells (DCs) displaying pronounced proinflammatory properties in the pathogenesis of multiple sclerosis (MS). Methods: We determined the presence of slanDCs in demyelinated brain lesions and CSF samples of patients with MS. In addition, we explored the impact of methylprednisolone, interferon-β, glatiramer acetate, or natalizumab on the frequency of blood-circulating slanDCs in patients with MS. We also evaluated whether interferon-β modulates important proinflammatory capabilities of slanDCs. Results: SlanDCs accumulate in highly inflammatory brain lesions and are present in the majority of CSF samples of patients with MS. Short-term methylprednisolone administration reduces the percentage of slanDCs in blood of patients with MS and the proportion of tumor necrosis factor-α- or CD150-expressing slanDCs. Long-term interferon-β treatment decreases the percentage of blood-circulating slanDCs in contrast to glatiramer acetate or natalizumab. Furthermore, interferon-β inhibits the secretion of proinflammatory cytokines by slanDCs and their capacity to promote proliferation and differentiation of T cells. Conclusion: Accumulation of slanDCs in highly inflammatory brain lesions and their presence in CSF indicate that slanDCs may play an important role in the immunopathogenesis of MS. The reduction of blood-circulating slanDCs and the inhibition of their proinflammatory properties by methylprednisolone and interferon-β may contribute to the therapeutic efficiency of these drugs in patients with MS.
    Full-text · Article · Oct 2014
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    ABSTRACT: Background aims Reactivation of cytomegalovirus (CMV) after hematopoietic stem cell transplantation remains a major cause of morbidity despite improved antiviral drug therapies. Selective restoration of CMV immunity by adoptive transfer of CMV-specific T cells is the only alternative approach that has been shown to be effective and non-toxic. We describe the results of clinical-scale isolations of CMV-specific donor lymphocytes with the use of a major histocompatibility (MHC) class I peptide streptamer-based isolation method that yields minimally manipulated cytotoxic T cells of high purity. Methods Enrichment of CMV-specific cytotoxic T lymphocytes (CTLs) was performed by labeling 1 × 1010 leukocytes from a non-mobilized mononuclear cell (MNC) apheresis with MHC class I streptamers and magnetic beads. Thereafter, positively labeled CMV-specific CTLs were isolated through the use of CliniMACS (magnetic-activated cell sorting), and MHC streptamers were released through the use of d-biotin. The purity of enriched CMV-specific CTLs was determined on the basis of MHC streptamer staining and fluorescence-activated cell sorting. Results A total of 22 processes were performed with the use of five different MHC class I streptamers. The median frequency of CMV-specific CTLs in the starting apheresis product was 0.41% among CD3+ T cells. The isolation process yielded a total of 7.77 × 106 CMV-specific CTLs, with a median purity of 90.2%. Selection reagents were effectively removed from the final cell product; the CMV-specific CTLs displayed excellent viability and cytotoxicity and were stable for at least 72 h at 4°C after MNC collection. Conclusions Clinical-scale isolation of “minimally manipulated” CMV-specific donor CTLs through the use of MHC class I streptamers is feasible and yields functional CTLs at clinically relevant dosages.
    Full-text · Article · Sep 2014 · Cytotherapy
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    ABSTRACT: In-depth analysis of the cellular and molecular mechanisms regulating human HSC function will require a surrogate host that supports robust maintenance of transplanted human HSCs in vivo, but the currently available options are problematic. Previously we showed that mutations in the Kit receptor enhance engraftment of transplanted HSCs in the mouse. To generate an improved model for human HSC transplantation and analysis, we developed immune-deficient mouse strains containing Kit mutations. We found that mutation of the Kit receptor enables robust, uniform, sustained, and serially transplantable engraftment of human HSCs in adult mice without a requirement for irradiation conditioning. Using this model, we also showed that differential KIT expression identifies two functionally distinct subpopulations of human HSCs. Thus, we have found that the capacity of this Kit mutation to open up stem cell niches across species barriers has significant potential and broad applicability in human HSC research.
    Full-text · Article · Jul 2014 · Cell Stem Cell
  • No preview · Article · Mar 2014 · Haematologica
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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.
    Full-text · Article · Mar 2014 · Journal of Cellular and Molecular Medicine
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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.
    Full-text · Article · Feb 2014 · Biomacromolecules
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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.
    Preview · Article · Dec 2013 · Clinical and Developmental Immunology
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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.
    Full-text · Article · Dec 2013 · OncoImmunology
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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.
    Full-text · Article · Nov 2013 · Journal of Tissue Engineering and Regenerative Medicine
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    ABSTRACT: Introduction: Adoptive transfer of human bone marrow mesenchymal stromal cells (BM-MSCs) in the context of post-transplant GvHD relies on their immunosuppressive abilities, which are still not fully characterized. Recently, an important role for the CD39-CD73-adenosine pathway in mediating immunosuppression was demonstrated in Tregs. Within this pathway extracellular nucleotides are phosphohydrolised to generate immunosuppressive adenosine. Since BM-MSCs express CD73 and recent data indicate that BM-MSCs express CD39, we decided to further investigate the CD39 expression in BM-MSCs and check whether inhibition of extracellular nucleotide phosphohydrolysis by POM-1 would impact not only on immunosuppressive capacity, but also on colony forming ability and differentiation potential. Methods: Expression of CD39 in BM-MSC lines was assessed by flow cytometry, immunocytochemistry and western blotting. With the aim to check whether CD39 would influence immunosuppressive properties of MSCs, anti- CD39 monoclonal antibody OREG-103/BY40 (CD39mAb) and a selective inhibitor of ENTPD 1 (CD39), 2 and 3, POM-1, were used within standardized immunosuppressive assays, such as the lymphocyte proliferation assay (LPA) and mixed lymphocyte reaction (MLR). For the colony forming unit (CFU-F) capacity, and in vitro differentiation potential into osteoblasts and adipocytes, POM-1 was used in 2 different concentrations (2 and 20µM). Results: All tested BM-MSC lines (n=20) expressed CD39 (19.2±3.3% CD39+ cells among BM-MSCs). Flow cytometric results were confirmed by immunocytochemistry as well as western blotting. Notably, addition of POM-1 significantly impaired the immunosuppressive capacity of BM-MSCs (at the concentration of 20 µM for the LPA and 2 µM for the MLR) in both assays (n=6, mean inhibition (MI) of 24.28±8.3% for the LPA; n=4, MI of 42.28±9.33% for the MLR) as compared to the non-treated BM-MSCs (MI of 70.2±2.7% for the LPA, p<0.0001; MI of 78.1±3.11% for the MLR, p=0.0015). Preliminary results using the CD39mAb indicate that the immunosuppressive capacity of BM-MSCs is reduced, confirming our results with POM-1. Furthermore, inhibition of ENTPDases by addition of POM-1 to the cultures hampered the colony formation ability of BM-MSCs (n=3). Interestingly, we also demonstrated that POM-1-mediated inhibition of ENTPdases resulted in compromised BM-MSCs differentiation potential. Conclusions: Here, we demonstrated that chemical inhibition of ENTPDases impairs the immunosuppression mediated by MSCs. Regarding the blockade of CD39 using a monoclonal antibody, we could observe preliminary effects that should be further analyzed. Moreover, our results suggested for the first time that ENTPDases has an important function in colony formation ability as well as in differentiation potential of MSCs. These novel findings improve our understanding of the mechanistic role of ENTPDases in MSC function and thus can contribute to the amelioration of MSC-based therapies for the treatment of autoimmune diseases as well as their use in regenerative medicine.
    No preview · Conference Paper · Sep 2013
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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.
    Full-text · Article · Aug 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    Full-text · Article · Aug 2013 · Blood Cancer Journal
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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.
    No preview · Article · May 2013 · Haematologica
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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.
    No preview · Article · Mar 2013 · International Journal of Cancer

Publication Stats

3k Citations
606.45 Total Impact Points

Institutions

  • 2009-2016
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany
  • 1998-2015
    • Technische Universität Dresden
      • Institute of Immunology
      Dresden, Saxony, Germany
  • 2000-2013
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 1997-1999
    • Johannes Gutenberg-Universität Mainz
      • • III. Department of Medicine
      • • Institut für Physiologische Chemie
      Mayence, Rheinland-Pfalz, Germany
    • Radboud University Nijmegen
      • Department of Biochemistry
      Nymegen, Gelderland, Netherlands