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Experimental Immunocardiology

Our research is focused at exploring the role of the innate and adaptive immunity in the pathogenesis of non-ischemic heart failure with main interest in inflammatory cardiomyopathy, diabetic cardiomyopathy and heart failure with preserved ejection fraction. The relevance of the cardiosplenic axis, i.e. homing of immune cells towards the heart and their subsequent involvement in cardiac remodelling is studied. Our further interest is the characterization of interactions among immune cells and cardiac endothelial cells, cardiac fibroblasts, and cardiomyocytes, as well as the reciprocal interactions among the cardiac cells.

The second focus of our research lies on evaluating the potential of immunomodulating strategies to treat or prevent inflammatory, diabetic cardiomyopathy or heart failure with preserved ejection fraction. In this regard, we investigate the potential of systemic delivery of cardiac-derived proliferating cells (CardAPs; cells isolated and characterized at the BCRT in conjunction with platform C, Tissue Engineering and D, Immune System), mesenchymal stromal cells, or T regulatory cells as well the potential of immunomodulatory pharmaca.

With the aim to translate our findings into the clinic, our observations in patients and patients material (endomyocardial biopsies, serum, circulating mononuclear cells) are further validated in in vivo and in vitro models and vice versa. Therefore, the group of experimental cardioimmunology is strongly interconnected with the cardioproteomics and clinical cardioimmunology groups.

Research Focus

  • Pattern recognition receptors including NOD-like receptors
  • Cardiosplenic axis
  • Immunomodulating strategies: cell-based and pharmacological strategies

Methods

Patient material

  • Characterization of endomyocardial biopsies via immunohistochemistry, gene expression analysis, outgrowth culture of cardiac fibroblasts
  • Characterization of transcoronary gradients via flow cytometry
  • Identification of circulating fibrocytes, apoptotic endothelial cells, mononuclear cell subsets,… via flow cytometry

Cell isolation, culture and in vitro models

  • Primary culture of human endomyocardial-biopsy-derived and mouse left ventricle-derived cardiac fibroblasts
  • Isolation and culture of murine cardiac mononuclear cells, splenocytes, peripheral blood mononuclear cells
  • Stress models: Coxsackievirus B3-, Parvovirus B19-, hyperglycemia-, angiotensin II-, tumor necrosis factor-α-, transforming growth factor-ß-induced stress
  • Culture of mesenchymal stromal cells, HUVEC, HAEC, HL-1 cardiomyocytes, THP-1 cells
  • Co-cultures of mesenchymal stromal cells / with HL-1 cardiomyocytes, cardiac fibroblasts, endothelial cells, co-culture of endothelial cells with HL-1 cardiomyocytes, co-culture of splenocytes with fibroblasts, co-culture of mononuclear cells and endothelial cells,…
  • Gene expression knockdown via siRNA transfection

Phalloidin (red)- and DAPI (blue, nucleus)-stained mesenchymal stromal cells showing actin filaments.

Animal models

  • Experimental models of viral-induced inflammatory cardiomyopathy, myocardial infarction, diabetic cardiomyopathy, angiotensin II-induced cardiac hypertrophy
  • Left ventricular function measurements by conductance catheter
  • Endothelial function analysis via organ water bath method

 

Organ water bath

 

Representative picture of an isolated mouse heart

  

Cooperations

  • Prof. Dr. Bart De Geest, Center for Molecular & Vascular Biology, Catholic University of Leuven, Leuven, Belgium
  • Prof. Dr. Wolfgang Linke, University of Bochum, Bochum
  • Dr. Nazha Hamdani, University of Bochum, Bochum
  • Dr. Henry Fechner and Dr. Sandra Pinkert, TU, Berlin
  • Prof. Dr. Kurreck, TU, Berlin
  • PD Dr. Martina Seifert, BCRT, Charité - Universitätsmedizin Berlin
  • Prof. Dr. Hans-Dieter Volk, BCRT, Charité - Universitätsmedizin Berlin
  • Prof. Michael Sittinger, Dr. Marion Haag, Dr. Jochen Ringe, BCRT, Charité - Universitätsmedizin
  • Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
  • PD Anna Foryst-Ludwig, AG Kintscher, Center for Cardiovascular Research (CCR), Berlin

Selected Publications

  • Spillmann F, Miteva K, Pieske B, Tschöpe C, Van Linthout S. High-Density Lipoproteins Reduce Endothelial-to-Mesenchymal Transition. Arterioscler Thromb Vasc Biol. 2015;35:1774-7.
  • Van Linthout S, Tschöpe C, Schultheiss HP. Lack in treatment options for virus-induced inflammatory cardiomyopathy: can iPS-derived cardiomyocytes close the gap? Circ Res. 2014;115:540-1.
  • Savvatis K*, Van Linthout S*, Miteva K, Pappritz K, Westermann D, Schefold JC, Fusch G, Weithäuser A, Rauch U, Becher PM, Klingel K, Ringe J, Kurtz A, Schultheiss HP, Tschöpe C. Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis. PLoS One;7:e41047.
  • Miteva K, Haag M, Peng J, Savvatis K, Becher PM, Seifert M, Warstat K, Westermann D, Ringe J, Sittinger M, Schultheiss HP, Tschöpe C*, Van Linthout S*. Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis. PLoS One. 2011;6:e28513.
  • Van Linthout S*, Savvatis K*, Miteva K, Peng J, Ringe J, Warstat K, Schmidt-Lucke C, Sittinger M, Schultheiss HP, Tschöpe C. Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis. Eur Heart J. 2011;32:2168-78.

 *Equal contribution.