AG Penack

+49 30 450 513 634

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PD Dr. Olaf Penack
t: +49 30 450 513 436
f: +49 30 450 553 914

AG Penack

The aim of our clinical studies and preclinical research is to increase knowledge in the field of transplantation biology. My lab is working on the development of strategies for prevention and treatment of acute graft-versus-host-disease (GVHD) after hematopoietic stem cell transplantation (HSCT). One specific focus is the role of the endothelium for HSCT biology. The main topics of our clinical research are GVHD and infectious diseases in immunocompromised hosts.  

Preclinical Projects

Angiogenesis during GVHD

 

An interesting novel therapeutic concept with potential simultaneous impact on tumor growth and inflammatory processes is the inhibition of Angiogenesis. We have demonstrated that the inhibition of inflammation-associated angiogenesis ameliorates GVHD by reducing the recruitment of tissue infiltrating leukocytes. Recently, we published data showing that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and GVHD, implicating that angiogenesis has an active role during the initiation of inflammation. In further steps, we are investigating cellular and molecular mechanisms of initial angiogenesis after allo-HSCT. Eventually, we aim at translational development of anti-angiogenic therapies to simultaneously reduce GVHD and tumor growth after allo-HSCT. 

 

 

Published article “Initiation of acute graft-versus-host disease by angiogenesis” on Blood Cover Vol 129, Issue 14: 1887-2038. Showing representative immunofluorescence staining of a proliferating Ki67+ (red) CD31+ (green) endothelial cell in the colon of a mouse recipient at day +2 after allogeneic bone marrow transplantation. By Riesner et al.

 

 

Lymphangiogenesis during GVHD

Lymph vessels play a crucial role for immune reactions in health and disease. The inhibition of lymphangiogenesis is an established therapeutic concept in oncology, which has entered clinical trials stage. During allogenic tissue transplantation the inhibition of lymphangiogenesis has been used to attenuate graft rejection. We are currently using murine allo-HSCT models and patient biopsies to demonstrate that acute GVHD is associated to lymphangiogenesis. We are studying the effect of monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) on lymphangiogenesis, GVHD, tumor growth, immune reconstitution and survival in murine allo-HSCT models.

    

   

 

 

 

Increased Density of Lymphatic Vessels during GVHD. Anti-Lyve1 stained  (green) colon sections demonstrate a higher lymph vessel density in recipients of an allo-HSCT as compared with recipients of a syn-HSCT

 

 

 

Cathepsin E and Dendritic Cell Motility during GVHD

We are interested in improving our understanding about the molecular mechanisms in the initiation phase of GVHD. Several insights into inflammatory processes have been gained from recent research, which show that interactions between microbial associated molecules (pathogen associated molecular patterns, PAMPs) and innate immune receptors (pathogen recognition receptors, PRRs) control adaptive immune responses in inflammatory disorders. We are working on one mechanism that can better explain the connection between microbial products and inflammation. We are currently studying the role of Cathepsin E (Ctse), an aspartate protease known to cleave bacterial peptides for antigen presentation in dendritic cells (DCs), for GVHD. During experimental acute GVHD, we find infiltration by Ctse positive immune cells in target organs. In Ctse deficient allo-SCT recipients, we find ameliorated GVHD, improved survival and lower numbers of tissue infiltrating DCs. Our current data suggest that Ctse has a previously unrecognized role in regulating DC motility, which we are planning to study in more detail.

 

 

Increased Ctse Expression in Colon during GVHD. Anti-Ctse stained (green) colon sections demonstrate more Ctse+ immune cells in colon tissue during GVHD as compared with syngeneic controls. 

 

 

 

Effect of Green Tea on GVHD

 

Recent research demonstrated that epigallocatechin gallate (EGCG), a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. We are currently studying the underlying mechanisms of EGCG-mediated GVHD regulation.

   

Reduced Inflammation in GVHD Target Organs after EGCG Treatment. Shown are H&E stains of colon tissue. Lymphocyte infiltration is reduced after EGCG Treatment. CL: Crypt loss, CA: Crypt apoptosis 

 

 

 

Enhancement of Endothelial Regeneration and Endothelial Function during GVHD

 

The endothelium is the first contact for immunological effector cells in the blood and key to the regulation of various inflammatory processes. Recent studies suggested that endothelial dysfunction and endothelial damage are critical factors for the development and severity of GVHD. Endothelial dysfunction during GVHD, as well as the mechanisms leading to endothelial dysfunction, have not been well characterized. In a collaborative research project between Charité University Medicine Berlin and Institut de Recerca contra la Leucèmia Josep Carreras / Hospital Clinic Campus Barcelona, we are planning to characterize endothelial damage and test strategies to enhance endothelial regeneration after allo-HSCT.

 

  

 

Schematic involvement of endothelium during GVDH (Penack and Helms)

        

Memory Cells and the Vascular Niche after HSCT

Two major obstacles to a more favorable therapeutic outcome of allo-HSCT are fatal infections and tumor relapse. Both complications are facilitated by long-term immune incompetence, which is known to be caused by HSCT. Mechanisms leading to HSCT-related long term immune incompetence are incompletely understood. Dr. Na’s group recently found, that acute GVHD affects thymus and bone marrow, leading to delayed T and B cell reconstitution. Memory cell deficiency after HSCT leads to a high susceptibility to fatal infections and therefore strategies to overcome this long-lasting immunodeficiency are required. Recently, it has been demonstrated that the BM is a reservoir for memory T and B cells, which are antigen-experienced immune cells crucial for immunity against a broad variety of pathogens. Memory T cells are maintained in close proximity to BM blood vessels suggesting endothelial cells to be part of the memory cell survival niche. In a collaborative research project between the research groups of Il-Kang Na and Olaf Penack, we aim to characterize the memory T and B cell reconstitution after syngeneic (syn) and allo-HSCT and to elucidate the role of the BM vasculature for the memory T and B cell survival in the BM. Furthermore, we will test immunotherapeutical and pharmacological strategies to improve the regeneration of the BM vasculature in order to facilitate accelerated seeding and maintenance of memory T and B cells into the BM and to provide thereby long-term immunity after HSCT.

BM Vasculature in a Murine GVHD Model. Shown are an anti-endomucin (yellow), anti-CD44 (red) and anti-CD4 (cyan) stains of the femoral bone. Nuclei are Dapi-stained (blue).

 

 

 

Use of Lycium barbarum polysaccharide (LBP) after allo-HSCT

                                                                                               Goji Berries, which are used to produce LBP

Although it has only been introduced in Western countries in recent years, Goji berry has been used for thousands of years in China, both as a culinary ingredient and medicinally. It has been reported that Goji berry contains natural anti-inflammatory, anti-bacterial and anti-fungal compounds. Their powerful antioxidant properties and Lycium barbarum polysaccharides (LBP) help to boost the immune system. It’s no wonder then, that in traditional Chinese medicine they are renowned for increasing strength and longevity. It has been reported that LBP has anticancer effect and could induce the apoptosis of human cancer cells. It was also found that macrophages, rather than T and B cells, are the principal immunostimulatory target cells of the LBP. We have established collaborations with different Chinese universities to study the mechanisms of the effect of LBP with our animal models.

                          

Publikationen

Publications Preclinical

  • Endothelial damage is aggravated in acute GvHD and could predict its development. Mir E, Palomo M, Rovira M, Pereira A, Escolar G, Penack O, Holler E, Carreras E, Diaz-Ricart M.Bone Marrow Transplant. 2017 Jun 26.
  • The Role of Lymphangiogenesis and its Inhibition during Graft-versus-Host Disease. Mertlitz S, Shi Y, Kalupa M, Grötzinger C, Mengwasser J, Riesner K, Cordes S, Elezkurtaj S, Penack O. Blood. 2017 Mar 30;129(13):1865-1875
  • Initiation of acute graft-versus-host disease by angiogenesis. Riesner K, Shi Y, Jacobi A, Kraeter M, Kalupa M, McGearey A, Mertlitz S, Cordes S, Schrezenmeier J.F, Mengwasser J, Westphal S, Perez-Hernandez D, Schmitt C, Dittmar G, Guck J, Penack O. Blood. 2017 Apr 6;129(14):2021-2032
  • Cathepsin E regulates dendritic cell motility during graft-versus-host disease. Mengwasser J, Babes L, Cordes S, Mertlitz S, Riesner K, Shi Y, McGearey A, Kalupa M, Reinheckel T, Penack O. Front Immunol. 2017 Mar 1;8:203
  • The green tea catechin EGCG ameliorates GVHD. Westphal S, Wilke A, Rudloff S, Penack O. 2016. PLoS One. 2017 Jan 19;12(1):e0169630
  • Organ siderosis and hemophagocytosis during acute graft-versus-host disease. Nogai A, Shi Y, Pérez-Hernandez D, Cordes S, Mengwasser J, Mertlitz S, Riesner K, Kalupa M, Erdmann JH, Ziebig R, Dittmar G, Penack O. Haematologica. 2016 Aug;101(8):e344-6.
  • VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors.Röhrig F, Vorlová S, Hoffmann H, Wartenberg M, Escorcia FE, Keller S, Tenspolde M, Weigand I, Gätzner S, Manova K, Penack O, Scheinberg DA, Rosenwald A, Ergün S, Granot Z, Henke E. Oncogene. 2016 Jun 6. doi: 10.1038/onc.2016.182.
  • A preclinical acute GVHD mouse model based on chemotherapy conditioning and MHC-matched transplantation. Riesner K, Kalupa M, Shi Y, Elezkurtaj S, Penack O. Bone Marrow Transplant. 2016 Mar;51(3):410-7.
  • Anti-tumor effects of anti-T-cell globulin. Westphal S, Brinkmann H, Kalupa M, Wilke A, Seitz-Merwald I, Penack O. Exp Hematol. 2014 Oct;42(10):875-82.
  • PLZF confers effector functions to donor T cells that preserve graft-versus-tumor effects while attenuating GVHD. Ghosh A, Holland AM, Dogan Y, Yim NL, Rao UK, Young LF, West ML, Singer NV, Lee H, Na IK, Tsai JJ, Jenq RR, Penack O, Hanash AM, Lezcano C, Murphy GF, Liu C, Sadelain M, Sauer MG, Sant'angelo D, van den Brink MR. Cancer Res. 2013 Aug 1;73(15):4687-96.
  • Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. Ghosh A, Dogan Y, Moroz M, Holland AM, Yim NL, Rao UK, Young LF, Tannenbaum D, Masih D, Velardi E, Tsai JJ, Jenq RR, Penack O, Hanash AM, Smith OM, Piersanti K, Lezcano C, Murphy GF, Liu C, Palomba ML, Sauer MG, Sadelain M, Ponomarev V, van den Brink MR. J Clin Invest. 2013 Jun;123(6):2654-62.
  • Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100. Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F, Fani M, Riesner K, Prinz G, Hechinger AK, Gerlach UV, Dierbach H, Penack O, Schmitt-Gräff A, Finke J, Weber WA, Zeiser R. Blood. 2013 Apr 25;121(17):3307-18.
  • Danger signals activating innate immunity in graft-versus-host disease. Zeiser R, Penack O, Holler E, Idzko M. J Mol Med (Berl). 2011 Sep;89(9):833-45.
  • The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. Penack O, Socié G, van den Brink MR. Blood. 2011 Apr 21;117(16):4181-9.
  • Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation. Lu SX, Kappel LW, Charbonneau-Allard AM, Atallah R, Holland AM, Turbide C, Hubbard VM, Rotolo JA, Smith M, Suh D, King C, Rao UK, Yim N, Bautista JL, Jenq RR, Penack O, Na IK, Liu C, Murphy G, Alpdogan O, Blumberg RS, Macian F, Holmes KV, Beauchemin N, van den Brink MR. PLoS One. 2011;6(7):e21611.
  • Absence of P-selectin in recipients of allogeneic bone marrow transplantation ameliorates experimental graft-versus-host disease. Lu SX, Holland AM, Na IK, Terwey TH, Alpdogan O, Bautista JL, Smith OM, Suh D, King C, Kochman A, Hubbard VM, Rao UK, Yim N, Liu C, Laga AC, Murphy G, Jenq RR, Zakrzewski JL, Penack O, Dykstra L, Bampoe K, Perez L, Furie B, Furie B, van den Brink MR. J Immunol. 2010 Aug 1;185(3):1912-9.
  • Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. Penack O, Henke E, Suh D, King CG, Smith OM, Na IK, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Lu TT, May C, Scheinberg DA, Gao DC, Mittal V, Heller G, Benezra R, van den Brink MR. J Natl Cancer Inst. 2010 Jun 16;102(12):894-908.
  • Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Penack O, Holler E, van den Brink MR. Blood. 2010 Mar 11;115(10):1865-72.
  • The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. Na IK, Lu SX, Yim NL, Goldberg GL, Tsai J, Rao U, Smith OM, King CG, Suh D, Hirschhorn-Cymerman D, Palomba L, Penack O, Holland AM, Jenq RR, Ghosh A, Tran H, Merghoub T, Liu C, Sempowski GD, Ventevogel M, Beauchemin N, van den Brink MR. J Clin Invest. 2010 Jan;120(1):343-56.
  • NOD2 regulates hematopoietic cell function during graft-versus-host disease. Penack O, Smith OM, Cunningham-Bussel A, Liu X, Rao U, Yim N, Na IK, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Brandl K, van den Brink MR. J Exp Med. 2009 Sep 28;206(10):2101-10.

Publications Clinical

  • EASIX in patients with acute graft-versus-host disease: a retrospective cohort analysis. Luft, T., Benner, A., Jodele, S., Dandoy, C. E., Storb, R., Gooley, T., Sandmaier, B. M., Becker, N., Radujkovic, A., Dreger, P. and Penack, O. Lancet Hematology 2017. In press.
  • Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016. Ullmann AJ, Schmidt-Hieber M, Bertz H, Heinz WJ, Kiehl M, Krüger W, Mousset S, Neuburger S, Neumann S, Penack O, Silling G, Vehreschild JJ, Einsele H, Maschmeyer G; Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology (AGIHO/DGHO) and the DAG-KBT (German Working Group for Blood and Marrow Transplantation). Ann Hematol. 2016 Sep;95(9):1435-55
  • Organ siderosis and hemophagocytosis during acute graft-versus-host disease. Nogai A, Shi Y, Pérez-Hernandez D, Cordes S, Mengwasser J, Mertlitz S, Riesner K, Kalupa M, Erdmann JH, Ziebig R, Dittmar G, Penack O. Haematologica. 2016 Aug;101(8):e344-6.
  • CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)-Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). Schmidt-Hieber M, Silling G, Schalk E, Heinz W, Panse J, Penack O, Christopeit M, Buchheidt D, Meyding-Lamadé U, Hähnel S, Wolf HH, Ruhnke M, Schwartz S, Maschmeyer G. Ann Oncol. 2016 Jul;27(7):1207-25
  • Anti-Aspergillus immunoglobulin-G testing in serum of hematopoietic stem cell transplant recipients. Erdmann JH, Graf B, Blau IW, Fischer F, Timm G, Hemmati P, Arnold R, Penack O. Transpl Infect Dis. 2016 Jun;18(3):354-60
  • Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties. Penack O, Tridello G, Hoek J, Socié G, Blaise D, Passweg J, Chevallier P, Craddock C, Milpied N, Veelken H, Maertens J, Ljungman P, Cornelissen J, Thiebaut-Bertrand A, Lioure B, Michallet M, Iacobelli S, Nagler A, Mohty M, Cesaro S. Bone Marrow Transplant. 2016 Mar;51(3):418-23
  • Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome. Radujkovic A, Becker N, Benner A, Penack O, Platzbecker U, Stölzel F, Bornhäuser M, Hegenbart U, Ho AD, Dreger P, Luft T. Oncotarget. 2015 Oct 27;6(33):35095-106
  • Antiviral prophylaxis in patients with solid tumours and haematological malignancies--update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Sandherr M, Hentrich M, von Lilienfeld-Toal M, Massenkeil G, Neumann S, Penack O, Biehl L, Cornely OA. Ann Hematol. 2015 Sep;94(9):1441-50.
  • Association between low uric acid levels and acute graft-versus-host disease. Ostendorf BN, Blau O, Uharek L, Blau IW, Penack O. Ann Hematol. 2015 Jan;94(1):139-44
  • Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease. Rachakonda SP, Penack O, Dietrich S, Blau O, Blau IW, Radujkovic A, Isermann B, Ho AD, Uharek L, Dreger P, Kumar R, Luft T. J Clin Oncol. 2014 Oct 20;32(30):3421-7
  • Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Tacke D, Buchheidt D, Karthaus M, Krause SW, Maschmeyer G, Neumann S, Ostermann H, Penack O, Rieger C, Ruhnke M, Sandherr M, Schweer KE, Ullmann AJ, Cornely OA. Ann Hematol. 2014 Sep;93(9):1449-56
  • Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO). Vehreschild JJ, Böhme A, Cornely OA, Kahl C, Karthaus M, Kreuzer KA, Maschmeyer G, Mousset S, Ossendorf V, Penack O, Vehreschild MJ, Bohlius J; Infectious Diseases Working Party of the Society for Haematology and Medical Oncology. Ann Oncol. 2014 Sep;25(9):1709-18.
  • Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO). Penack O, Becker C, Buchheidt D, Christopeit M, Kiehl M, von Lilienfeld-Toal M, Hentrich M, Reinwald M, Salwender H, Schalk E, Schmidt-Hieber M, Weber T, Ostermann H. Ann Hematol. 2014 Jul;93(7):1083-95. doi
  • Central venous catheter-related infections in hematology and oncology: 2012 updated guidelines on diagnosis, management and prevention by the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology. Hentrich M, Schalk E, Schmidt-Hieber M, Chaberny I, Mousset S, Buchheidt D, Ruhnke M, Penack O, Salwender H, Wolf HH, Christopeit M, Neumann S, Maschmeyer G, Karthaus M; Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology. Ann Oncol. 2014 May;25(5):936-47.
  • Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Mousset S, Buchheidt D, Heinz W, Ruhnke M, Cornely OA, Egerer G, Krüger W, Link H, Neumann S, Ostermann H, Panse J, Penack O, Rieger C, Schmidt-Hieber M, Silling G, Südhoff T, Ullmann AJ, Wolf HH, Maschmeyer G, Böhme A. Ann Hematol. 2014 Jan;93(1):13-32

Drittmittelförderung

  • Deutsche Forschungsgemeinschaft
  • Deutsche Krebshilfe
  • Else Kröner Fresenius-Stiftung
  • José Carreras Leukämie-Stiftung
  • Wilhelm Sander-Stiftung