Visual Universitätsmedizin Mainz

Research Team Prof. Dr. Steinbrink

Division for Experimental and Translational Immunodermatology

The Division for Experimental and Translational Immunodermatology (DETI) under the direction of Prof. Dr. Kerstin Steinbrink is a unique institute aiming at bringing basic science, preclinical studies, and therapeutic developments from bench to bedside in the field of immunodermatology. Clinical activities are focused on inflammatory and autoimmune dermatoses and the patients are treated in the outpatients unit for autoimmune diseases in the Department of Dermatology. This entails strong links to the Center of Autoimmune Diseases at the University Medical Center Mainz and encompasses the access to modern therapeutic strategies, i.a. in the context of clinical studies.

Our group focusses on the analyses of mechanisms of immunological tolerance to develop innovative therapeutic strategies for allergic and autoimmune disease and cancer in the long run. Deep knowledge in tolerance processes and their induction and modulation may result in improved treatments for patients suffering from inflammatory and autoimmune dermatoses and cancer. The DETI is embedded in the Research Center of Immunotherapy (FZI) of the University Medical Center Mainz and exhibit close cooperations with the Center of Thrombosis and Hemostasis (CTH), institutes of the Faculty of Chemistry, and the Max Planck Institutes for Chemistry and Polymer Chemistry.

Head:

Univ.-Prof. Dr. med. Steinbrink
Kerstin Steinbrink, Univ.-Prof. Dr. med.

+49 (0)6131-177130
+49 (0)6131-175527
kerstin.steinbrink@unimedizin-mainz.de

Foto_II_30-06-2016.tif
DSC_Autoimmunsprechstunde.jpg

Research topics

  • tolerance induction as therapy for allergic and autoimmune diseases
  • innate and adaptive immune system and type I and IV allergies
  • nanoparticle-based immunotherapy
  • microbiome and immunity

Innate immune signals and their effect on adaptive hapten-specific immune responses

We developed a low zone tolerance (LZT) model, in which repeated applications of low doses of contact allergens impede the development of contact hypersensitivity (CHS; the murine form of an allergic contact dermatitis). The LZT reaction is based on a process in which tolerance is induced by the sequential generation of allergen-specific regulatory CD4+ and CD8+ T cells (Tregs). In the current project, we focus on studies to analyse the mechanisms of the innate immunity and their effects on adaptive hapten-specific immune responses (oral and epicutaneous LZT, CHS). The function of immune cells of the early phase and/or pattern recognition receptor-mediated mechanisms of the immune response and the influence of the microbiome will be analysed with special regard on the induction function of regulatory CD4+CD25+  and CD8+  T cell responses.
Funded within the by Transregio 156

SFB_Logo__1_.jpg
Transregio_CHS_LZT_2016.tif

The role of early inflammatory processes in systemic fibrosis (scleroderma)

Systemic fibrosis is a arre autoimmune disease characterized by vascular alterations and an excessive production of collagen which leads to thickening of connective tissues. Progessed fibrosis is irreversible and can not be treated efficiently to date.
The mechanisms during the early phase of scleroderma induction particularly with regard to associated inflammatory processes have been scarcely adressed so far. Aim of the project is to analyse the immune processes involved in experimental models of scleroderma focussing on the early inflammatory phase of the disease.
In cooperation with the working group of Prof. Dr. Detlef Schuppan (Institute for Translational Immunology) the role of macrophages and dendritic cells as well as molecules and signaling pathways associated with the pathogenesis are addressed,
Furthermore we aim to shed light on the role of platelets and the coagulation cascade in scleroderma in close cooperation with the working group of Prof. Wolfram Ruf head of the Centrum for Thrombosis and Hemostasis (CTH) in Mainz.
Insight into relevant vascular and immunological mechanisms and the cell populations /target structures involved could help to establish more effective treatment options for scleroderma.
Funded within the by Transregio 156

SFB_Logo__1_.jpg
Transregio_Scl.jpg

Inhibition of IL-10- and STAT3-mediated, tumor-associated tolerance mechanisms with functionalized nanoparticles

Cell-type specific drug delivery by use of nanoparticles has become a promising approach for the induction of efficient anti-tumor responses in cancer immunotherapy due to an increase of efficacy and a reduction of side effects. However, attempts to boost the immune system against the tumor often fail as tolerance induction by tumor cells within the tumor microenvironment plays a critical role in tumor progression and tremendously weakens the success of cancer immunotherapy. For instance, tumor cells can induce tolerance by the induction of tolerogenic dendritic cells or regulatory T cells. Those cell types exhibit a broad range of immunosuppressive functions which further enhance tumor escape. In this context, IL-10- and STAT3-mediated pathways are important mechanisms of immunological tolerance. In close collaboration with Prof. Dr. K. Landfester (Max Planck Institute for Polymer Chemistry), we plan to inhibit those IL-10- and STAT3-mediated, tumor-associated tolerance mechanisms in tolerogenic dendritic cells or regulatory T cells, respectively, by using functionalized nanoparticles with the capability of drug delivery (small molecules, siRNA) to abolish tolerance induction.
This project is funded by the SFB1066 and the Max Planck Graduate Center of the Johannes Gutenberg-University Mainz

sfb1066.jpg
header_image_sans_rightMPGC_logo_Matthias.jpg
SFB1066_Tumor_project.png

Tissue factor and protease-activated receptor 2 signaling in cutaneous inflammation


Tissue factor (TF) and protease-activated receptor 2 (PAR2) regulate cardiovascular function, hemostasis and thrombosis. They also act in (cutaneous) inflammation, but the exact interplay with innate and adaptive immune cells is poorly understood. PAR2 is mainly activated by proteolytic cleavage of extracellular proteases that also include the binary complex of TF and activated factor VII (VIIa).
Here, we investigate the role of TF and PAR2 in contact hypersensitivity (CHS) as a murine model for allergic contact dermatitis in humans. Functionally active TF is blocked by an anti-TF antibody in vivo. Also, several transgenic mouse strains are used: PAR2 receptor mutant mice, PAR2fl/fl mice and TFfl/fl mice. Our read-out parameters are the ear swelling in vivo, the cellular infiltrate of the ear (assessed by histology and flow cytometry) and the hapten-specific T cell response (assessed by T cell proliferation and T cell cytokine production).
In a translational study with patients that suffer from allergic contact dermatitis we measure the cell-specific expression of TF and PAR2 by immunofluorescence and flow cytometry to identify correlating processes in humans.
This project is a joint project with Wolfram Ruf’s group from the Center for Thrombosis and Hemostasis, CTH, University Medical Center Mainz. This project is funded by the CTH.

cth.png
CTH_Project.tif

Analysis of the induction of allergen-specific tolerance in patients with type I allergies

Pollen-allergic patients frequently develop pollen-associated food allergies. However, up to now, appropriate therapy approaches are not available that affected both, the pollen- as well as food-allergy-related symptoms. Within this project, influences of tolerance-inducing IL-10-treated human dendritic cells loaded with recombinant pollen and food allergen on the resulting T cell responses with focus of induction of cross-reactive tolerance will be elucidated. With regard to cross-allergies of pollen-allergic patients to food allergens, induction of allergen-specific (cross-tolerance) by IL-10DC will be analyzed. This study may allow for the development of an innovative prophylactic and/or therapeutic treatment of type-I-allergies based on (cross-) tolerance induction. Funded by the German Research Foundation.

dfg_logo_.jpg
DFG_Allergy.jpg
raker_klein.JPG

Dr. rer. nat. Verena K. Raker
Laboratory Head

Tel: +49 6131 17-2297 (lab)
Tel: +49 6131 17-6143 (office)
FAX: +49 6131 17-5505
E-Mail:  rakerv@uni-mainz.de
Curriculum Vitae (C.V.) (Pdf-file, 30,1 KB)

schmidgen_klein.JPG

Dr. med. Maria Isabel Schmidgen
Postdoc, Clinician Scientist

Tel: +49 6131 17-4284 (lab)
Tel: +49 6131 17-6143 (office)
FAX: +49 6131 17-5505
E-Mail:  maria_isabel.schmidgen@unimedizin-mainz.de
Curriculum Vitae (C.V.) (Pdf-file, 537,3 KB)

schmidt_klein.JPG

Dr. rer. nat. Talkea Schmidt
Postdoc

Tel: +49 6131 17-4284 (lab)
Tel: +49 6131 17-6142 (office)
FAX: +49 6131 17-5505
E-Mail:  talkea.schmidt@unimedizin-mainz.de
Curriculum Vitae (C.V.) (Pdf-file, 43,0 KB)

graulich_klein.JPG

Edith Graulich
Technical Assistant

Tel:  +49 6131 17-2297 (lab)
FAX: +49 6131 17-5505
E-Mail:  edith.graulich@unimedizin-mainz.de

lorenz_klein.JPG

Nadine Röhrig
Technical Assistant

Tel:  +49 6131 17-4284 (lab)
FAX: +49 6131 17-5505
E-Mail:  nadine.roehrig@unimedizin-mainz.de

domogalla_klein.JPG

M.Sc. Matthias Philipp Domogalla
PhD Student

Tel: +49 6131 17-2297 (lab)
Tel: +49 6131 17-5323 (office)
FAX: +49 6131 17-5505
E-Mail:  matthias.domogalla@unimedizin-mainz.de
Curriculum Vitae (C.V.) (Pdf-file, 73,6 KB)

haub_klein.JPG

M.Sc. Jessica Haub
PhD Student

Tel: +49 6131 17-4284 (lab)
Tel: +49 6131 17-5323 (office)
FAX: +49 6131 17-5505
E-Mail:  jessica.haub@unimedizin-mainz.de

hares_klein.JPG

B.Sc. Tina Hares
Master Student

Tel: +49 6131 17-2297 (lab)
FAX: +49 6131 17-5505
E-Mail:  thares@students.uni-mainz.de

rostan_klein.JPG

Patricia Rostan
PhD Student

Tel: +49 6131 17-2297 (lab)
Tel: +49 6131 17-5323 (office)
FAX: +49 6131 17-5505
E-Mail:  patricia.rostan@unimedizin-mainz.de
Curriculum Vitae (C.V.) (Pdf-file, 50,9 KB)

References (selected):

1. Steinbrink K., E. Macher, and C. Sorg. Low zone tolerance to contact allergens in mice: a functional role for CD8+ T helper type 2 cells. J. Exp. Med., 183: 759-768, 1996.

2. Steinbrink, K., M. Wölfl, H. Jonuleit, J. Knop, and A.H. Enk. Induction of tolerance by interleukin-10-treated dendritic cells. J. Immunol., 159: 4772-4780, 1997.

3. Steinbrink, K., H. Jonuleit, G. Müller, G. Schuler, J. Knop, and A.H. Enk. IL-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8+ T cells resulting in a failure to lyse tumor cells. Blood, 93, 5: 1634-1642, 1999.          

4. Steinbrink, K., E. Graulich, S. Kubsch, J. Knop, and A. H. Enk. CD4+ and CD8+ anergic T cells induced by IL-10-treated human dendritic cells display antigen-specific suppressor activity. Blood, 99: 2468-2476, 2002.

5. Kubsch, S., E. Graulich, J. Knop, and K. Steinbrink. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1.Eur. J. Immunol., 33: 1988-1997, 2003.            

6. Maurer M., W. Seidel-Guyenot, M. Metz, J. Knop, and K. Steinbrink. Critical role of IL-10 in the induction of low zone tolerance to contact allergens. J. Clin. Invest., 112: 432-439, 2003.  

7. Seidel-Guyenot W., R. Alt, S. Perschon, J. Knop and K. Steinbrink. B cells are not required for T cell priming in low zone tolerance to contact allergens and contact hypersensitivity. Eur. J. Immunol., 34: 3082-3090, 2004.   

8. Seidel-Guyenot, W., S. Perschon, N. Dechant, R. Alt, and K. Steinbrink. Low zone tolerance induced by systemic application of allergens inhibits Tc1-mediated skin inflammation. J. Allergy Clin. Immunol, 117: 1170-1177, 2007.             

9. Adler H., S. Kubsch, E. Graulich, S. Ludwig, J. Knop, and K. Steinbrink. Activation of MAP kinase p38 is critical for the regulatory function of anergic T cells induced by tolerogenic dendritic cells. Blood. 109: 4351-4359, 2007.                                                 

10. Adler, H, A. Simon, E. Graulich, A. Habermeier, N. Bacher, A. Friebe, E. I. Closs, and K. Steinbrink. Neuronal nitric oxide synthase modulates maturation of human dendritic cells. J. Immunol., 184: 6025-6034, 2010.                                           

11. Bacher N., E. Graulich, H. Jonuleit, S. Grabbe, and K. Steinbrink. Interferon-a abrogates tolerance induction by human tolerogenic dendritic cells. PLoS ONE, 10.1371, 2011.           

12. Luckey U., M. Maurer T. Schmidt, N. Lorenz, B. Seebach, M. Metz and K.  Steinbrink. T cell killing by tolerogenic dendritic cells protects from allergy in mice. J. Clin. Invest., 121: 3860-3871, 2011. In Research Highlights, Nat. Rev. Immunol. Oktober 2011

13. Luckey, U., T. Schmidt, N. Pfender, N. Lorenz, S.F. Martin, E. Schmitt, T. Jakob, and K. Steinbrink. Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in low zone tolerance.  J. Allergy Clinical. Immunol., 130:781-797, 2012.          

14. Frick S.U., N. Bacher, G. Baier, V. Mailänder, K. Landfester, and K. Steinbrink. Functionalized polystyrene nanoparticles trigger human dendritic cell maturation resulting in enhanced CD4+ T cell activation. Macromol. Biosci. doi: 10.1002/i.201200223, 2012.        

15. Hofmann C., S. Scheurer, K. Rost,  E. Graulich,  A. Jamin, K. Foetisch,  J. Saloga, S. Vieths, K. Steinbrink*, and H.S. Adler*. Cor a 1-reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen-associated food allergy to hazelnut. *contributed equally as senior authors J. Allergy Clin. Immunol., 131:1384-1392, 2013.   

16. Bacher N., V. Raker, C. Hofmann,  E. Graulich, M. Schwenk, R. Baumgrass, T. Bopp, U. Zechner, L.  Merten, C. Becker, and K. Steinbrink. Interferon-a suppresses cAMP to disarm human regulatory T cells. Canc. Res., 73:5647-56, 2013.                                  

17. Schmidt T., N. Lorenz, V. Raker, S. Reißig, A. Waisman, B. Weigmann, and K. Steinbrink. Epicutaneous and oral low zone tolerance protects from colitis in mice. J. Invest. Dermatol. 136(9):1831-9, 2016.

18. Raker V.K., K. Yong Ook, J. Haub, N. Lorenz, T. Schmidt, A. Stegemann, M. Böhm, D. Schuppan, and K. Steinbrink. Myeloid cell population and fibrogenic parameters in bleomycin- and HOCl-induced fibrosis. Exp. Dermatol.  doi: 10.1111/exd.13124 2016.

19. Kryczanowsky F, Raker V, Graulich E, Domogalla MP, Steinbrink K. IL-10-Modulated Human Dendritic Cells for Clinical Use: Identification of a Stable and Migratory Subset with Improved Tolerogenic Activity. J. Immunol., Sep 28. pii: 1501769, 2016.

20. Frick SU, Domogalla MP, Baier G, Wurm FR, Mailaender V, Landfester K, Steinbrink K. Interleukin-2 Functionalized Nanocapsules for T Cell-Based Immunotherapy. ACS Nano,. Oct 10, 2016.