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Alexander/Hiepe lab
New ways of approaching treatment of autoimmune diseases
Autoimmunology
Our research group is fundamentally involved in analysing the mechanisms which contribute to and help maintain severe autoimmune diseases in order to develop new therapeutic concepts.
Our main focus is on the role of long-lived autoreactive plasma cells in autoimmune diseases. Long-lived plasma cells reside in niches in the bone marrow and inflamed tissues, where they are resistant to immunosuppressive/cytotoxic drugs or therapies targeting B cells. In collaboration with the research group from Andreas Radbruch, we look for new therapeutic strategies targeting the autoreactive memory. We introduced the proteasome inhibitor bortezomib that depletes plasma cells in the treatment of refractory autoimmune diseases. We also learned that selective plasma cell depletion has to be combined with a therapy targeting the plasma cell precursors to prevent the generation of new plasma cells. Since all these therapies unselectively deplete plasma cells, regardless whether they secrete protective of pathogenic antibodies, we developed an affinity matrix technology for antigen-specific plasma cell depletion. Recently, we could show for the first time that long-lived memory plasma cells can be depleted in an antigen-specific manner using this technology in a murine model. One current study is aimed to demonstrate an improvement of muscle weakness in a murine model of myasthenia gravis after the specific depletion of plasma cells secreting autoantibodies against the acetylcholine receptor.
Together with the Unit for Bone Marrow Transplantation (Renate Arnold) at the Charité – Universitätsmedizin Berlin, and the research group of Andreas Thiel (BCRT), we demonstrated that the autoreactive memory could be eliminated by immunoablation followed by autologous hematopoietic stem cell transplantation, in patients with severe autoimmune diseases that are refractory to conventional immunosuppression. In most cases this provided the basis for the subsequent regeneration of an intact immune system. In some patients, however, the disease relapsed, or secondary autoimmune disorders occurred. We investigate the reasons for this in a controlled clinical trial in systemic lupus erythematosus (SLE).
In another project, we study the role of dendritic cells in SLE. These cells, in their function as antigen-presenting cells and producers of cytokines, play a significant role in the pathogenesis of SLE. As they are a potential target in the development of new therapies, their characterisation is of major relevance.
Several cytokines are involved in the pathogenesis of SLE and other systemic autoimmune diseases. In past and future clinical trials, we have studied biologics selectively targeting different cytokines or cells (e.g. BAFF/BLys, APRIL, type I interferon, IL-10, B cells, PDC, co-stimulatory molecules). We expect that these different therapeutic approaches will allow us to develop personalised therapies.
Along similar lines, we have developed several novel biomarkers, reflecting specific aspects of the pathogenesis of SLE. We have identified serologic (autoantibodies) and cellular biomarkers (Siglec1 expression on monocytes, B and T cell subpopulations in the peripheral blood and urinary immune cells). We believe these biomarkers will enable us to tailor make our treatment in the future for patients and broaden our understanding of the disease pathogenesis.
Keywords
Memory plasma cells
Autoantibodies
Systemic autoimmune diseases
Cellular therapies
Autologous hematopoietic stem cell transplantation
Group leader
PD Dr. med. Tobias Alexander
Prof. Dr. med. Falk Hiepe
Scientists
Qingyu Cheng, PhD
PD Dr. med.Philipp Enghard (Guest scientist)
Laleh Khodadadi, PhD
Dr. med. Lennard Ostendorf
Dr. med. Thomas Rose
PhD students
Dilara Cirillo
Deborah Puppe
Sarnai Naran
MD students
Anne Elisabeth Beenken
Hannah Brandt
Paul Freund
Nina Görlich
Jacob Kujat
Dominik Lammerding
Spyridon Lipka
Jonas Martin
Christopher Skopnik
Konrad Speidel
Lena Teichert
Univ.-Prof. Dr. med. Renate Arnold, Charité – Universitätsmedizin Berlin, CVK, Med. Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany
Prof. Dr. Klemens Budde and Dr. Michael Dürr, Charité – Universitätsmedizin Berlin, CCM, Medizinische Klinik m.S. Nephrologie, Berlin, Germany
Prof. Dr. Richard Burt, Northwestern University, Department of Medicine, Division of Immunotherapy, Chicago, USA
Univ.-Prof. Dr. med. Thomas Dörner, Charité – Universitätsmedizin Berlin, CCM, Medizinische Klinik m.S. Rheumatologie und Klin. Immunologie, Berlin
Univ.-Prof. Dr. Peter M. Kloetzel, Charité – Universitätsmedizin Berlin, Institut für Biochemie, Berlin, Germany
Univ.-Prof. Dr. Rudolf Manz, Universität zu Lübeck, Institut für Systemische Entzündungsforschung ISEF, Lübeck, Germany
Prof. Dr. Edgar Meinl, Institut für Klinische Neuroimmunologie, Ludwig Maximilian Universität München, Germany
Prof. Dr. Andreas Meisel and Dr. Siegfried Kohler, Klinik für Neurologie, Charité – Universitätsmedizin Berlin, Germany
Prof. Dr. med. Thomas Porstmann, Seramun Diagnostica GmbH, Heidesee, Germany
Prof. Dr. Michael Reth, Max-Planck-Institut für Immunbiologie, Freiburg. Germany
Dr. Jürgen Schmitz, Dr. Andrzej Dzionek, Dr. Barbara Behle, Miltenyi Biotech, Bergisch Gladbach, Germany
Dr. Wolfgang Schlumberger, EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany
Prof. Dr. David Tarlinton, Walter und Eliza-Hall-Institut für Medizinische Forschung, Melbourne, Australia
Univ.-Prof. Dr. med. Reinhard E. Voll, Universitätsklinikum Freiburg, Med. Klinik, Abteilung Rheumatologie und Klinische Immunologie, Freiburg, Germany
Prof. Dr. rer. nat. Hedda Wardemann, DKFZ, Heidelberg, Germany
Univ.-Prof. Dr. med. Margitta Worm, Charité – Universitätsmedizin Berlin, CCM, Klinik für Dermatologie, Venerologie und Allergologie, Berlin, Germany
- Scheibe, F., H. Pruss, A. M. Mengel, S. Kohler, A. Numann, M. Kohnlein, K. Ruprecht, T. Alexander, F. Hiepe, and A. Meisel. 2017. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 88: 366-370.
- Wilhelm, T. R., A. Taddeo, O. Winter, A. R. Schulz, J. N. Malzer, C. Domingo, R. Biesen, T. Alexander, A. Thiel, A. Radbruch, F. Hiepe, and V. Gerl. 2016. Siglec-1-positive plasmacytoid dendritic cells (pDCs) in human peripheral blood: A semi-mature and myeloid-like subset imbalanced during protective and autoimmune responses. Clin Immunol 163: 42-51.
- Hiepe, F., and A. Radbruch. 2016. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol 12: 232-240.
- Taddeo, A., V. Gerl, B. F. Hoyer, H. D. Chang, S. Kohler, H. Schaffert, A. Thiel, A. Radbruch, and F. Hiepe. 2015. Selection and depletion of plasma cells based on the specificity of the secreted antibody. Eur J Immunol 45: 317-319.
- Khodadadi, L., Q. Cheng, T. Alexander, O. Sercan-Alp, J. Klotsche, A. Radbruch, F. Hiepe, B. F. Hoyer, and A. Taddeo. 2015. Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice. PloS one 10: e0135081.
- Alexander, T., R. Sarfert, J. Klotsche, A. A. Kuhl, A. Rubbert-Roth, H. M. Lorenz, J. Rech, B. F. Hoyer, Q. Cheng, A. Waka, A. Taddeo, M. Wiesener, G. Schett, G. R. Burmester, A. Radbruch, F. Hiepe, and R. E. Voll. 2015. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 74: 1474-1478.
