CRC Transregio 221|Projects

Project B01

 

Therapeutic targeting of T-follicular cells in GvHD

Site: Würzburg, Erlangen
Principal Investigator: PD Dr. rer. nat. Friederike Berberich-Siebelt, PD Dr. med. Silvia Spörl

Summary Project B01

Calcineurin inhibitors block NFAT activation and protect patients from graft-versus-host disease during bone marrow transplantation. On the other hand, they exert adverse side effects and interfere with the valuable graft-versus-leukemia effect. In contrast, NFAT deficiency maintains graft-versus-leukemia activity, although still protecting from graft-versus-host disease in mouse models. Therefore, it is planned to evaluate new NFAT inhibitors in vitro, on engineered human skin and in mouse models, as well as to ablate NFAT family members by CRISPR/Cas9 ahead of cell transfer.

 

Contact to Principal Investigator

PD Dr. rer. nat Friederike Berberich-Siebelt

PD Dr. med. Silvia Spörl

Universität Würzburg

University Hospital Erlangen

Institut für Pathologie

Department of Medicine 5

Josef-Schneider-Straße 2

Ulmenweg 18

97080 Würzburg

91054 Erlangen

T: 0931 31-81208

T: +49 9131 8545021

path230(at)mail.uni-wuerzburg.de

silvia.spoerl(at)uk-erlangen.de

Project B02

 

Targeting of TNFR2 and related molecules to separate GvHD from the GvL effect

Site: Würzburg
Principal Investigator: Prof. Dr. rer. nat. Harald Wajant

Summary Project B02

Previously, we demonstrated in mice that targeting of TNFR2 and Fn14 allows GvL effect-sparing inhibition of GvHD by different mechanisms. Now, we will clarify whether co-targeting of TNFR2 and Fn14 yields additive or even synergistic therapeutic activity. To facilitate clinical translation of TNFR2 targeting on Tregs, we will also develop human TNFR2-specific antibody variants with Fcγ-receptor-independent agonistic activity and various IL-2 receptor targeted TNFR2 agonists. These reagents will be tested and evaluated in a variety of in vitro models but also in knockin mice in which the ectodomain of murine TNFR2 has been replaced by the corresponding domain of human TNFR2.

 

Contact to Principal Investigator

Prof. Dr. rer. nat. Harald Wajant

University Hospital Würzburg

Department of Medicine II

Molecular Internal Medicine

Röntgenring 11

97070 Würzburg

T: +49 931 201-71000

harald.wajant@mail-uni-wuerzburg.de

Project B03

 

Generation, molecular characteristics and effector mechanisms of CSF2+-T-cells in graft-versus-host disease.

Site: Erlangen 
Principal Investigator: Prof. Dr. med. Kai Hildner

Summary Project B03

CSF2+ T cells have been recently described to critically mediate immune-mediated tissue-damage in various autoimmune disease models. Their role within the pathogenesis of GvHD has not been studied yet. Our results indicate that CSF2+ donor T cells critically contribute to intestinal GvHD manifestation suggesting that CSF2 might represent a novel drugable target to limit GvHD. Hence, the overall goal of this research project is to molecularly and functionally define the T cell-extrinsic and -intrinsic signals that drive CSF2+ donor T cell formation and identify the characteristics and effector mechanisms of CSF2+ donor T cells in the immune pathogenesis of GvHD.

 

Contact to Principal Investigator

Prof. Dr. med. Kai Hildner

University Hospital Erlangen

Department of Medicine 1

Ulmenweg 18

91054 Erlangen

T: +49 9131 85-35000 o. 85-45173

kai.hildner(at)uk-erlangen.de

Project B04

 

Aldehyde dehydrogenase 3A2 (ALDH3A2) as a novel regulator of inflammation and fibrotic tissue remodeling in sclerodermatous chronic graft-versus-host-disease

Site: Erlangen 
Principal Investigators: Prof. Dr. med. Jörg Distler, PD Dr. med. Regina Jitschin, PhD

Summary Project B04

Metabolic deregulation is emerging as a common pathogenic driver of chronic inflammatory as well as fibrosing diseases. We demonstrated in our preliminary resultsthat the expression of ALDH3A2 is deregulated in the skin of cGvHD patients in a TGFb-dependentmanner. Inactivation of ALDH3A2 prevented fibroblast activation, whereas overexpression of ALDH3A2 promoted collagen release and deposition of extracellular matrix. Moreover, inactivation of ALDH3A2 modulated leukocyte infiltration and ameliorated tissue remodelingin the murine cGvHD. With the current project, we aim to study the effects of ALDH3A2 on leukocyteinfiltration and fibroblast activation in experimental cGvHD and to decipher the molecular mechanisms, by which ALDH3A2 regulates inflammation and tissue remodeling in cGvHD.

 

Contact to Principal Investigators

Prof. Dr. med. Jörg Distler

PD Dr. med. Regina Jischin, PhD

University Hospital Erlangen

University Hospital Erlangen

Department of Medicine 3

Department of Medicine 5

Ulmenweg 18

Ulmenweg 18

91054 Erlangen

91054 Erlangen

T: +49 9131 85-43008

T: +49 9131 8543113

joerg.distler(at)uk-erlangen.de

regina.jitschin(at)uk-erlangen.de

Project B07

 

GvHD therapy with in vitro expanded donor regulatory T cells.

Site: Regensburg
Principal Investigators: PD Dr. rer. nat. Petra Hoffmann, Prof. Dr. rer. nat. Michael Rehli, Prof. Dr. med. Matthias Edinger

Summary Project B07

We previously showed that donor CD4+CD25+Foxp3+ regulatory T cells (Treg) prevent lethal acute GvHD after MHC-mismatched BMT in murine models. We now observed that they also ameliorate ongoing GvHD and the prerequisites for efficacious GvHD therapy are studied in this project. For this purpose, the migration pattern of in vitro expanded donor Treg is examined, their organ-specific T cell receptor (TCR) repertoire selection and their site-specific functional status. Finally, we investigate whether their therapeutic efficacy in GvHD can be enhanced by the overexpression of alloreactive TCRs or tissue-specific homing receptors.

 

Contact to Principal Investigators

PD Dr. rer. nat. Petra Hoffmann

Prof. Dr. rer. nat. Michael Rehli

Prof. Dr. med. Matthias Edinger

LIT - Leibniz Institute for Immunotherapy (former RCI)

University Hospital Regensburg

University Hospital Regensburg

c/o Universitätsklinikum Regensburg

Department of Internal Medicine III

Department of Internal Medicine III

Franz-Josef-Strauß-Allee 11

Franz-Josef-Strauß-Allee 11

Franz-Josef-Strauß-Allee 11

93053 Regensburg

93053 Regensburg

93053 Regensburg

T: +49 941 944-38492

T: +49 941 944-38487

T: +49 941 944-5582

petra.hoffmann(at)ukr.de

michael.rehli(at)ukr.de

matthias.edinger(at)ukr.de

Project B08

 

Harnessing tissue homeostasis-promoting functions of specialized regulatory T cells in graft-versus-host disease.

Site: Regensburg
Principal Investigator: Prof. Dr. med. Markus Feuerer

Summary Project B08

Regulatory T cells (Treg) perform two distinct functions: they maintain self-tolerance and support organ homeostasis by differentiation into specialized tissue Treg cells. We aim to harness the tissue-repair, organ-homeostasis promoting function of tissue-resident Treg cells to prevent or treat graft-versus-host disease after allogeneic bone marrow transplantation. In this respect, we study a TH2-biased tissue Treg population that is present in virtually all organs. We will use loss-of-function and gain-of-function experiments to understand how these cells function during GvHD. Finally, we want to translate these findings into the human context.

 

Contact to Principal Investigator

Prof. Dr. med. Markus Feuerer

LIT - Leibniz Institute for Immunotherapy (former RCI)

c/o Universitätsklinikum Regensburg

Franz-Josef-Strauß-Allee 11

93053 Regensburg

T: +49 941 944-38121

markus.feuerer(at)ukr.de

Project B09

 

Non-classical monocyte-derived intestinal myeloid cells in allo-HSCT - Biology and therapeutic applications.

Site: Würzburg
Principal Investigator: Prof. Dr. med. Dr. med. univ. Andreas Beilhack, Dr. rer. nat. Mercedes Gomez de Agüero

Summary Project B09

Based on our recent findings on the spatio-temporal kinetics of graft-versus-host disease (GvHD) pathophysiology we discovered a regulatory myeloid cell population that exerts protective functions during the intestinal GvHD effector phase. Employing preclinical mouse models for GvHD and GvL we will interrogate the identity, mechanism of action, and therapeutic potential of this immune-protective myeloid cell subset to improve allo-HSCT.

Contact to Principal Investigator

Prof. Dr. med. Dr. med. univ. Andreas Beilhack

Dr. rer. nat. Mercedes Gomez de Agüero

Universitätsklinikum Würzburg

Julius-Maximilians-University Würzburg

Medizinische Klinik und Poliklinik II

Würzburg Institute für Systemimmunologie

ZEMM Zentrum für Experimentelle Molekulare Medizin

Versbacher Straße 9

Zinklesweg 10

97078 Würzburg

97078 Würzburg

T: +49 931 80303

T: 0931 201-44040

mercedes.gomes(at)uni-wuerzburg.de

beilhack_a(at)ukw.de

 

Project B10

 

Dysregulation of the B-lymphocyte compartments leading to chronic GvHD

Sites: Erlangen & Regensburg
Principal Investigators: Prof. Dr. rer. nat. Thomas Winkler, Dr. med. Julia Winkler, Prof. Dr. med. Daniel Wolff

Summary Projects B10

Although experimental data point to a crucial role of antibody mediated damage in chronic GvHD clinical evidence remains restricted to associations but direct proof is lacking. Within the research program we will analyse clonal B cell subpopulations directly involved in clinical chronic GvHD, characterize host specific antibodies including identification of targets and glycosylation profile, analyse T follicular helper cells mediating this process and finally characterize B cell infiltration host-and donor-antibody mediated damage of target organs.

 

Contact to Principal Investigators

Prof. Dr. rer. nat. Thomas Winkler

Dr. med. Julia Winkler

Prof. Dr. med. Daniel Wolff

FAU Erlangen-Nürnberg

University Hospital Erlangen

University Hospital Regensburg

Department of Biology

Department of Medicine 5

Department of Internal Medicine III

Nikolaus-Fiebiger-Center for Molecular Medicine

Ulmenweg 18

Franz-Josef-Strauß-Allee 11

Glückstraße 6

91054 Erlangen

93053 Regensburg

91054 Erlangen

T: +49 9131 85-43112T: +49 941 944-5531

T: +49 9131 85-29136

julia.winkler(at)uk-erlangen.de

daniel.wolff(at)ukr.de

thomas.winkler(at)fau.de

  

Project B11

 

Targeting the reciprocal interaction of GvHD and atherosclerosis after allogeneic HSCT.

Site: Würzburg
Principal Investigators: Prof. Dr. med. Alma Zernecke, Prof. Dr. med. Dr. med. univ. Andreas Beilhack

Summary Project B11

Patients undergoing allogeneic HSCT have an increased risk of cardiovascular disease. To address the interconnection between GvHD and atherosclerosis, we will use a GvHD-atherosclerosis mouse model and analyze GvHD activity, plaque development, as well as local and systemic immune responses. We will further focus on monocytes/macrophages and CD8+ T cells in mediating vascular inflammation and GvHD using relevant knockout mice and/or cell depletion strategies. In addition, we will investigate the potential of immunosuppressive drugs to improve GvHD-related atherosclerosis. It is our aim to define novel approaches to reduce cardiovascular events after HSCT.

 

Contact to Principal Investigators

Prof. Dr. med. Alma Zernecke-Madsen

Prof. Dr. med. Dr. med. univ. Andreas Beilhack

University Hospital Würzburg

University Hospital Würzburg

Department of Experimental Biomedicine II

Department of Medicine II

Josef-Schneider-Straße 2

ZEMM Center for Experimental Molecular Medicine

97080 Würzburg

Zinklesweg 10

T: +49 931 201-48331

97078 Würzburg

alma.zernecke(at)uni-wuerzburg.de

T: +49 931 201-44040

 

beilhack_a(at)ukw.de

Project B12

 

Regulation of the immune balance during allogeneic hematopoietic stem cell transplantation by vitamin D3.

Sites: Regensburg & Erlangen
Principal Investigators: Prof. Dr. rer. nat. Marina Kreutz, PD Dr. rer. nat. Heiko Bruns

Summary Project B12

To understand the underlying mechanisms for the protective effects of vitamin D3 in allogeneic HSCT patients we will investigate vitamin D3-related changes in the microbiome, epithelial barrier function and immune cell infiltration in GvHD target tissues in murine GvHD models. In vitro-analyses will prove direct effects of vitamin D3 on the function of T cells and macrophages. Results will be confirmed in murine models after selective deletion of the vitamin D receptor in T cells, macrophages and epithelial cells. Finally, effector mechanisms will be verified in human GvHD samples. Results should provide the basis for vitamin D3 supplementation of allo-HSCT patients in a prospective clinical trial.

 

Contact to Principal Investigators

Prof. Dr. rer. nat. Marina Kreutz

PD Dr. rer. nat Heiko Bruns

University Hospital Regensburg

University Hospital Erlangen

Department of Internal Medicine III

Department of Medicine 5

Franz-Josef-Strauß-Allee 11

Ulmenweg 18

93053 Regensburg

91052 Erlangen

T: +49 941 944-5577

T: +49 9131 85-43163

marina.kreutz(at)ukr.de

heiko.bruns(at)uk-erlangen.de

Project B13

 

Enterococci in allogeneic stem cell transplantation – indicators of loss of diversity or true GvHD pathogens.

Site: Regensburg
Principal Investigators: PD Dr. med. Daniela Weber, Prof. Dr. med. Dr. rer. nat. André Gessner, Prof. Dr. med. Ernst Holler

Summary Project B13

Based on our previous observation, that high enterococcal abundance associates with GvHD, we aim to analyze the causal relationship between enterococci and GvHD. Enterococcal strains collected from GvHD patients will be tested for pathogenicity in epithelial cell cultures as well as in murine models of colitis and GvHD: GvHD will be induced after recolonization of mice pretreated with antibiotics or of germfree mice with apathogenic and highly pathogenic strains. Full sequencing and targeted mutagenesis of specific enterococcal strains will be performed to identify strain specific pathogenicity factors. Finally, the impact of enterocccci on intestinal Treg and IgA reconstitution will be analyzed.

 

Contact to Principal Investigators

PD Dr. med. Daniela Weber

Prof. Dr. med. Dr. rer. nat. André Gessner

Prof. Dr. med. Ernst Holler

University Hospital Regensburg

University Hospital Regensburg

University Hospital Regensburg

Department of Internal Medicine III

Department of Clinical Chemistry and Laboratory Medicine

Department of Internal Medicine III

Franz-Josef-Strauß-Allee 11

Franz-Josef-Strauß-Allee 11

Franz-Josef-Strauß-Allee 11

93053 Regensburg

93053 Regensburg

93053 Regensburg

T: +49 941 944-5510

T: +49 941 944-6401

T: +49 941 944-5542

daniela.weber(at)ukr.de

andre.gessner(at)ukr.de

ernst.holler(at)ukr.de