Juliane Ladhoff

Publications (6)33.78 Total impact

• Article: In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia.

  Yoshiaki Hara, Meaghan Stolk, Jochen Ringe, Tilo Dehne, Juliane Ladhoff, Katja Kotsch, Anja Reutzel-Selke, Petra Reinke, Hans-Dieter Volk, Martina Seifert
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  ABSTRACT: Brain death and prolonged cold ischemia are major contributors to the poorer long-term outcome of transplants from deceased donor kidney transplants, with an even higher impact if expanded criteria donors ('marginal organs') are used. Targeting ischemia-reperfusion injury-related intragraft inflammation is an attractive concept to improve the outcome of those grafts. As mesenchymal stem cells (MSCs) express both immunomodulatory and tissue repair properties, we evaluated their therapeutic efficacy in a rat kidney transplant model of prolonged cold ischemia. The in vitro immunomodulatory capacity of bone marrow-derived rat MSCs was tested in co-cultures with rat lymph node cells. For in vivo studies, Dark Agouti rat kidneys were cold preserved and transplanted into Lewis rats. Syngeneic Lewis MSCs were administered intravenously. Transplants were harvested on day 3, and inflammation was examined by quantitative RT-PCR and histology. Similarly to MSCs from other species, rat MSCs in vitro also showed a dose-dependent immunomodulatory capacity. Most importantly, in vivo administration of MSCs reduced the intragraft gene expression of different pro-inflammatory cytokines, chemokines, and intercellular adhesion molecule-1. In addition, fewer antigen-presenting cells were recruited into the renal allograft. In conclusion, rat MSCs ameliorate inflammation induced by prolonged cold ischemia in kidney transplantation.
  Transplant International 08/2011; 24(11):1112-23. · 2.92 Impact Factor
• Source

  Available from: Mir-Farzin Mashreghi

  Article: Effects of the new immunosuppressive agent AEB071 on human immune cells.

  Mareen Matz, Ulrike Weber, Mir-Farzin Mashreghi, Christine Lorkowski, Juliane Ladhoff, Stefan Kramer, Hans-H Neumayer, Klemens Budde
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  ABSTRACT: BACKGROUND. The novel immunosuppressive agent AEB071 is currently being evaluated for its capability to prevent rejection after kidney transplantation as a potential adjunct to calcineurin inhibitor-based regimen. AEB071 is a selective protein kinase C inhibitor and has been shown to be well tolerated in humans. We here present extensive in vitro studies that contribute to the understanding of AEB071 effects on human lymphocyte, natural killer (NK) cell and dendritic cell (DC) action. The impact of AEB071 on several T-cell activation and costimulatory markers was assessed. Furthermore, assays were performed to study the effect on T-cell proliferation and intracellular cytokine production. Additionally, the effect of AEB071 on DC maturation and their capacity to stimulate allogeneic T-cells was examined. Also, an evaluation of AEB071 effects on the lytic activity of human NK cells was performed. We were able to show that T-cell proliferation and cytokine production rates are significantly reduced after AEB071 administration. Also, mitogen-induced T-cell activation characterized by expression levels of surface markers could be significantly inhibited. In contrast, the T-cell stimulatory capacity of AEB071-treated mature monocyte-derived DC (Mo-DC) is not reduced, and AEB071 administration does not prevent lipopolysaccharide (LPS)-induced Mo-DC maturation. It could be demonstrated that AEB071 significantly inhibited the cytotoxic activity of NK cells. The promising immunosuppressive agent AEB071 has a strong impact on T-cell activation, proliferation and cytokine production as well as NK cell activity, but not DC maturation in vitro, and therefore, seems to function T-cell and NK cell specific via protein kinase C (PKC) inhibition.
  Nephrology Dialysis Transplantation 07/2010; 25(7):2159-67. · 3.40 Impact Factor
• Article: Immune privilege of endothelial cells differentiated from endothelial progenitor cells.

  Juliane Ladhoff, Bernhard Fleischer, Yoshiaki Hara, Hans-Dieter Volk, Martina Seifert
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  ABSTRACT: The application of autologous endothelial progenitor cells (EPC) is a promising approach in cardiovascular regeneration, but the availability of cells in appropriate numbers is the limiting factor. Allogeneic EPC would be an alternative, and we therefore analysed the immunogenicity of EPC-derived endothelial cells (EC) to evaluate their potential usefulness. Circulating EPC from rat were differentiated into EC and characterized phenotypically and functionally. Major histocompatibility complex (MHC) expression in response to interferon-gamma was determined compared with rat aortic EC, and in vitro humoral and cellular allogeneic responses were analysed. To determine the in vivo effects, acellular aortic grafts were endothelialized in vitro with EPC-derived EC and transplanted in a complete allogeneic mismatch rat aortic interposition model. EPC-derived EC expressed endothelial-specific markers and low levels of MHC class I (MHC I), but no constitutive MHC class II (MHC II). When stimulated with interferon-gamma, they upregulated MHC I and moderately upregulated MHC II. They were protected against alloantibody/complement-mediated lysis and allospecific cytotoxic T lymphocyte activity. They were less potent in allogeneic stimulation of CD4 T cells than aortic EC. Seeding of EPC-derived EC into acellular grafts led to excellent endothelialization, and allogeneic aortic transplantation induced only mild inflammatory responses without signs of rejection. EPC-derived EC are protected against allospecific cellular immune responses and humoral-mediated attacks in vitro. When transplanted in vivo as a component of vascular grafts, these cells are not rejected, which makes them useful in therapeutic applications, especially vascular reconstruction.
  Cardiovascular research 04/2010; 88(1):121-9. · 5.80 Impact Factor
• Article: Human immune responses to porcine xenogeneic matrices and their extracellular matrix constituents in vitro.

  Alexandra Bayrak, Maria Tyralla, Juliane Ladhoff, Martina Schleicher, Ulrich A Stock, Hans-Dieter Volk, Martina Seifert
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  ABSTRACT: Several tissue engineering approaches for the treatment of cardiovascular diseases are based on a xenogeneic extracellular matrix. However, the application of engineered heart valves has failed in some patients, causing severe signs of inflammation by so far undetermined processes. Therefore we investigated the immune-mediated responses to porcine valve matrices (native, decellularized and glutaraldehyde-fixed) and to purified xenogeneic extracellular matrix proteins (ECMp). The induction of human immune responses in vitro was evaluated by analyzing the co-stimulatory effects of matrices and ECMp collagen and elastin on the proliferation of immune cell sub-populations via CFSE-based proliferation assays. The pattern of cytokine release was also determined. In porcine matrix punches we demonstrated strong immune responses with the native as well as the decellularized type, in contrast to attenuated effects with glutaraldehyde-fixed matrices. Furthermore, our results indicate that collagen type I (porcine and human) and human elastin were able to elicit proliferation in co-stimulation with anti-CD3 antibody, accompanied by a strong release of Th1 cytokines (IFN-gamma, TNF-alpha). In contrast, porcine elastin did not elicit any response at all. This low immunogenic potential of porcine elastin suggests its suitability for the creation of new tissue engineering heart valve scaffolds in the future.
  Biomaterials 02/2010; 31(14):3793-803. · 7.40 Impact Factor
• Article: Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells.

  Juliane Ladhoff, Michael Bader, Sabine Brösel, Elke Effenberger, Dirk Westermann, Hans-Dieter Volk, Martina Seifert
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  ABSTRACT: Embryonic stem cells (ESC) are suggested to be immune-privileged, but they carry the risk of uncontrolled expansion and malignancy. Upon differentiation they lose their tumor-forming capacity, but they become immunogenic by the expression of a normal set of MHC molecules. This immunogenicity might trigger rejection after application in regenerative therapies. In this study MHC expression of and immune responses to endothelial derivatives of rat embryonic stem cell-like cells (RESC) under inflammatory conditions were determined in comparison to primary rat aortic endothelial cells (ECs). Cellular as well as humoral allo-recognition was analyzed in vitro. In addition, immune reactions in vivo were assessed by allo-antibody production and determination of interferon-gamma (IFNgamma)-secreting allo-reactive T cells. RESC derivatives expressed low but significant levels of MHC class I, and no MHC class II. In response to IFNgamma MHC class I expression was enhanced, while class II transactivator induction failed completely in these cells; MHC class II expression remained consistently absent. Functionally, the RESC derivatives showed a reduced allo-stimulatory capacity, protection against humoral allo-recognition in vitro and a slightly diminished susceptibility to cytotoxic T cell lysis. Furthermore, in vivo experiments demonstrated that these cells do not trigger host immune reactions, characterized by no allo-antibody production and no induction of allo-reactive memory T cells. Our results show that endothelial derivatives of RESC have a distinctive reduced immunogenic potency even under inflammatory conditions.
  Cell Research 03/2009; 19(4):507-18. · 8.19 Impact Factor
• Article: An anti-major histocompatibility complex class I intrabody protects endothelial cells from an attack by immune mediators.

  Cornelia Doebis, Sabine Schu, Juliane Ladhoff, Annette Busch, Florian Beyer, Jakob Reiser, Roberto F Nicosia, Sabine Broesel, Hans-Dieter Volk, Martina Seifert
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  ABSTRACT: In vitro endothelialization has significantly improved the overall outcome of artificial prostheses in cardiovascular bypass surgery. A drawback of this tissue-engineering method remains the limited availability of suitable autologous endothelial cells (EC), especially in aged patients. Allogeneic EC with high proliferative capacity represent a potentially valuable alternative to a patient-specific vascular transplant. However, such cells carry the risk of being rejected due to Major Histocompatibility Complex (MHC) mismatches. We investigated the effects of a very potent, intracellularly expressed antibody directed against MHC class I molecules, referred to as alpha-rat MHC I single chain variable fragment (sFv) intrabody. The intrabody was stably expressed in rat aortic EC (RAEC) following lentiviral vector-mediated gene transfer. The functional consequence of the MHC I down-regulation was tested in an allogeneic setting in two different in vitro assays. Stable expression of the alpha-rat MHC I sFv intrabody resulted in a highly efficient depletion of surface MHC I. Thereby those RAEC which displayed low MHC I levels over extended periods of time were protected against killing by allo-specific, cytotoxic T cells (CTL) and by allo-antibody/complement-mediated lysis. These results demonstrate that intrabody-mediated down-regulation of MHC I reduces the immunogenicity of RAEC which may provide a suitable alternative supply for the lining of vascular prostheses.
  Cardiovascular Research 12/2006; 72(2):331-8. · 6.06 Impact Factor