Experimental Rheumatology

Re-establishment of (immune) tolerance: a serious goal

Hamann

Introduction

Autoimmune/chronic-inflammatory disorders such as rheumatoid arthritis are characterized by an impaired regulation of the immune system. Mechanisms keeping the immunological tolerance are not properly working so that autoimmunity can develop, and in chronic inflammation the immune system becomes refractory to down-regulation and termination of inflammation. We study features of chronically activated, pathogenic T cells and their physiological counterpart, normal memory T cells. Our focus is on their epigenetic profiles that determine which functional properties become “imprinted”, i.e. epigenetically fixed. Additionally, we search for novel ways to improve mechanisms of tolerance and aim to identify factors such as small molecule drug candidates that act by inducing regulatory T cells (Tregs) or anti-inflammatory cytokines. Our goal is to translate general principles in immune regulation into novel strategies for the therapy of autoimmune/chronic inflammatory diseases.

Epigenetic imprinting of T cells and topographical memory

Upon initial activation, naive T cells differentiate into effector/memory T cells, a developmental state, which seems fixated by epigenetic imprinting. This includes modification of histones and DNA methylation and results in chromatin remodelling, which determines a certain gene activity state and contributes to a transcriptional memory. We could show that such mechanisms preserve stable expression of homing receptors that are crucial for the migration of T cells into distinct tissues and into sites of inflammation. As part of the German epigenome programme (DEEP) consortium, we now analyze genome-wide epigenetic signatures to identify candidate genes that are involved in development, differentiation and survival of normal or pathogenic human T cells from healthy donors and patients with rheumatic diseases, respectively. We generated full epigenomes from naive central memory cells and effector/memory cells from healthy donors that demonstrate e.g. global de-methylation with differentiation, but also reveal a number of promising epigenetically regulated candidate genes that might control T cell differentiation.

Immunoregulation, tolerance and immunotherapy

Regulatory T cells inhibit auto-specific cells in reacting against self-antigens. In patients with autoimmune diseases these mechanisms are disturbed. To improve natural self-tolerance, we search for novel approaches that are able to induce or expand Tregs. We developed a high-throughput screening assay to identify novel biological or chemical compounds able to induce Tregs. Furthermore, we engineered antigenic self-peptides by conjugation to macromolecular carriers so that they enhance Treg generation and thereby act as tolerogenic vaccine. We investigate how inflammatory processes become normally terminated when the immune system has successfully cleared pathogens. In this situation, pro-inflammatory cytokines become down-regulated and immunosuppressive mediators up-regulated. We could show that anti-inflammatory cytokines such as IL-27 play an important role for protection from uncontrolled tissue damage: Recombinant IL-27 treatment protected mice from fatal immunopathology during influenza infection. To develop novel drugs we are now searching for substances stimulating the production of the anti-inflammatory cytokines IL-27, IL-35, IL-37.

Selected Publications

1. Liu FD, Kenngott EE, Schröter MF, Kühl A, Jennrich S, Watzlawick R, Hoffmann U, Wolff T, Norley S, Scheffold A, Stumhofer JS, Saris CJ, Schwab JM, Hunter CA, Debes GF, Hamann A. 2014. Timed action of IL-27 protects from immunopathology while preserving defense in influenza. PLoS Pathog. 10(5): e1004110.

2. Pink M, Ratsch BA, Mardahl M, Schröter MF, Engelbert D, Triebus J, Hamann A, Syrbe U. 2014 Identification of two regulatory elements controlling Fucosyltransferase 7 transcription in murine CD4+ T cells. Mol Immunol. 62(1):1-9 3. Gupta S*, Pfeil J*, Kumar S, Poulsen C, Lauer U, Hamann A, Hoffmann U*, Haag R*. 2015. Tolerogenic modulation of the immune response by oligoglycerol- and polyglycerol-peptide conjugates. Bioconjug Chem. 26(4):669-79. (*contributed equally)

4. Watzlawick* R, Kenngott* EE, Liu FD, Schwab JM, Hamann A. 2015 Anti-Inflammatory Effects of IL-27 in Zymosan-Induced Peritonitis: Inhibition of Neutrophil Recruitment Partially Explained by Impaired Mobilization from Bone Marrow and Reduced Chemokine Levels. PLoS One. 10(9):e0137651 (*contributed equally)

5. Kenngott EE, Cole S, Hein WR, Hoffmann U, Lauer U, Maass D, Moore L, Pfeil J, Rosanowski S, Shoemaker CB, Umair S, Volkmer R, Hamann A, Pernthaner A. 2016. Identification of Targeting Peptides for Mucosal Delivery in Sheep and Mice. Mol Pharm. 13(1):202-10. (*contributed equally)

Members

 

Group leader
Prof. Dr. rer. nat. Alf Hamann

Scientists
Dr. Pawel Durek
Dr. Stefan Frischbutter
Dr. Ute Hoffmann
Dr. Julia Polansky-Biskup
PD Dr. Uta Syrbe*
* Med. Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie Charité – CBF Berlin

Ph.D. students
Dipl. Biol. Elisabeth Kenngott
M.Sci.Biochem. Christopher Kressler
Dipl. Biol. Matthias Kröger
M. Sci. Mol. Biol. Maybritt Mardahl
Dipl. Biol. Jennifer Pfeil
Dipl. Biochem. Julia Triebus

Diplom/Bachelor/Master-Students
Julia Bluhm
Melanie de Almeida,
Julia Hackbusch
Mario Simonetti,
Sabrina Schüngel
Olga Trupp
Aneta Ziolkowska

Technical assistance
Uta Lauer
René Maier

Students
Siska Wilantri
Nerve Cansu Iseri
Magdalena Maier
Anja Schaus
Nataliya Storozhylova

Cooperation partners

Dr. Stefan Bereswill, Dr. Markus Heimesaat, Charité – Universitätsmedizin Berlin, Institut für Mikrobiologie, Berlin, Deutschland

Celares GmbH, Berlin, Deutschland

Dr. Ho-Ryun. Chung - Max Planck Institut für Molekulare Genetik, Berlin, Deutschland

Dr. Wei Chen - Max Delbrück Zentrum für Molekulare Medizin, Berlin, Deutschland

Prof. Gudrun Debes, Prof. Chris Hunter, University of Pennsylvania, Dept. Pathobiology, Philadelphia, USA

Dr. Thomas Hanke, Evotec AG, Hamburg, Germany

Prof. Rainer Haag, Freie Universität, Institut für Chemie und Biochemie, Berlin, Deutschland

Prof. Susanne Hartmann, Dr. Svenja Steinfelder, Institut für Immunologie, Veterinärmedizin, FU Berlin, Deutschland

Prof. Andreas Herrmann, Humboldt-Universität, Institut für Biologie; Molekulare Biophysik, Berlin, Deutschland

Prof. Jochen Hühn, Dr. Stefan Flöß, Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Deutschland

Dr. Anja Kühl, Dr. Ulrike Erben, Charité – Universitätsmedizin Berlin, iPATH Berlin, RCIS, Berlin, Deutschland

Prof. Max Löhning, Prof. Alexander Scheffold, Charité – Universitätsmedizin Berlin, Medizinische Klinik für Rheumatologie, Berlin, Deutschland

Dr. Sven Olek, Dr. Udo Baron, Epiontis, Berlin, Deutschland

Dr. Antony Pernthaner, AG Research Ltd., Hopkirk Research Institute, Neuseeland

Prof. Thomas Schneider, Dr. Verena Moos, Prof. Dr. Britta Siegmund, Charité – Universitätsmedizin Berlin, Institut für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Deutschland

Prof. Tim Sparwasser, Twin Core, Institut für Infektionsimmunologie, MH Hannover, Deutschland

Prof. Jan Schwab, Prof. Andreas Meisel, Charité – Universitätsmedizin Berlin, Medizinische Klinik für Neurologie, Berlin; Deutschland

Prof. Birgit Sawitzki, Prof. Hans-Dieter Volk, Dr. Rudolf Volkmer, Charité – Universitätsmedizin Berlin, Institut für Medizinische Immunologie und BCRT, Berlin, Deutschland

Prof. Eckart Schott, Charité – Universitätsmedizin Berlin, Medizinische Klinik Hepatologie und Gastroenterologie, Berlin, Deutschland

Prof. Jörn Walter, Universität des Saarlandes, FB Genetik, Saarbrücken, Deutschland und andere Partner des DEEP Konsortiums

PD Dr. Thorsten Wolff, RKI, Berlin, Deutschland

PD Dr. Thomas Zollner, Dr. Nicole Schmidt, Bayer AG, Berlin, Deutschland

Prof. Dr. rer. nat. Alf Hamann

Deutsches Rheuma-Forschungszentrum Berlin
Experimental Rheumatology
Charitéplatz 1
10117 Berlin
Gemany

Phone +49 (0)30 28460 655
Fax +49 (0)30 28460-603
hamann@drfz.de

Keywords
Immune regulation
Therapy
Regulatory T cells
Epigenetics
Homing