Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment option for patients with high-risk leukemia and lymphoma and for certain inherited or acquired hematopoietic deficiencies. Around half a million transplantations have been performed to date and approximately 30 million voluntary stem cell donors are currently registered world-wide. The curative potential of allo-HSCT is based on the replace¬ment of the patient´s hematopoiesis by hematopoietic stem cells derived from a healthy donor and the immunologic eradication of residual patient hematopoietic cells by co-transplanted lymphocytes. This graft-versus-hematopoiesis reaction is mainly mediated by alloreactive donor T cells that also attack malignant hematopoietic cells, thereby evoking potent graft-versus-leukemia / lymphoma (GvL) effects. Although allo-HSCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of allo-HSCT recipients develop disease relapse or progression after transplantation. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses to prevent tumor escape. Yet, donor T cells can also attack solid organs, a transplant complication called graft-versus-host disease (GvHD) that can become life-threatening and in its acute form mainly affects skin, liver and gut. Therefore, it is the central goal of the TRR 221 to elucidate the immunological mechanisms of GvL and GvHD responses to increase the efficacy of allo-HSCT without increasing the risk for GvHD.To achieve this goal scientists of project area A analyzed new molecular targets and cellular pathways (e.g. T cell receptor & chimeric antigen receptor transfer, multifunctional antibodies, minor histocompatibility antigen-specific T cells) to augment GvL responses and assessed them in in vivo models (wherever reasonable) during the first funding period. In project area B involved scientists examined basic pathomechanisms of GvH-reactivity and develop new strategies for the prevention and/or therapy of this transplant complication. Here, the specific modulation of T cell signal transduction pathways is explored, regulatory molecular and cellular networks within innate and adaptive immune compartments are examined as well as GvHD-promoting co-factors, such as inflammatory pathways and microbiome alterations. Strategies aimed to strengthen GvL effects are always tested for their influence on GvHD and vice versa. The most promising strategies evolving from these studies shall be tested in future clinical trials to ultimately improve the safety and efficacy of allo-HSCT significantly.
DFG Programme
CRC/Transregios
Current projects
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A01 - Deciphering the role of HLA-DO in immune responses after allogeneic stem cell transplantation
(Project Heads
Kremer, Anita
;
Reimann, Hannah
)
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A02 - Efficacy and safety of HLA-DPB1-specific T cell receptors as mediators of graft-versus-leukemia effect
(Project Heads
Herr, Wolfgang
;
Thomas, Simone
)
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A03 - Advanced CAR T cell engineering to augment the graft-versus-leukemia effect of allogeneic HSCT
(Project Heads
Einsele, Hermann
;
Hudecek, Michael
)
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A04 - Novel tri-specific T-cell activating antibodies for personalized graft-versus-leukemia therapy
(Project Heads
Bargou, Ralf C.
;
Bumm, Thomas
;
Mokhtari, Ph.D., Zeinab
;
Stuhler, Gernot
)
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A06 - Metabolic stress related immune alterations with impact on graft-versus-leukemia effect in allogeneic stem cell transplantation
(Project Heads
Mackensen, Andreas
;
Mougiakakos, Dimitrios
)
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A07 - Enhancing graft-versus-leukemia responses by donor-derived CAR-modified CD8+ T memory stem cells
(Project Heads
Gattinoni, Luca
;
Harrer, Dennis
)
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A08 - Timed targeting of cGAS / STING to improve tissue-regeneration and anti-tumor responses following allo-HSCT
(Project Heads
Poeck, Hendrik
;
Schmidl, Christian
)
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B01 - Therapeutic targeting of T-follicular cells in GvHD
(Project Heads
Berberich-Siebelt, Friederike
;
Spörl, Silvia
)
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B02 - Targeting of TNFR2 and related molecules to separate GvHD from the GvL effect
(Project Head
Wajant, Harald Günther
)
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B03 - Generation, molecular characteristics and effector mechanisms of CSF2+ T cells in graft-versus-host disease
(Project Head
Hildner, Kai
)
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B04 - Aldehyde dehydrogenase 3A2 (ALDH3A2) as a novel regulator of inflammation and fibrotic tissue remodeling in sclerodermatous chronic graft-versus-host disease
(Project Heads
Distler, Jörg Hans Wilhelm
;
Jitschin, Ph.D., Regina
;
Spriewald, Bernd
)
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B07 - GvHD therapy with in vitro expanded donor regulatory T cells
(Project Heads
Edinger, Matthias
;
Hoffmann, Petra
;
Rehli, Michael
)
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B08 - Harnessing tissue homeostasis-promoting functions of specialized regulatory T cells in graft-versus-host disease
(Project Head
Feuerer, Markus
)
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B09 - Regulation of tissue-resident myeloid cells controling acute and chronic GvHD
(Project Heads
Beilhack, Andreas
;
Gomez de Agüero, Mercedes
)
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B10 - Dysregulation of the B-lymphocyte compartment leading to chronic GvHD
(Project Heads
Winkler, Thomas
;
Winkler, Julia
;
Wolff, Daniel
)
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B11 - Targeting the reciprocal interaction of GvHD and atherosclerosis after allogeneic HSCT
(Project Heads
Beilhack, Andreas
;
Zernecke-Madsen, Alma
)
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B12 - Regulation of the immune balance during allogeneic hematopoietic stem cell transplantation (HSCT) by vitamin D3
(Project Heads
Bruns, Heiko
;
Kreutz, Marina P.
;
Peter, Katrin
)
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B13 - Enterococci in allogeneic stem cell transplantation – indicators of loss of diversity or true GvHD pathogens?
(Project Heads
Gessner, Ph.D., André
;
Holler, Ernst
;
Weber, Daniela
)
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B14 - Role of EGF-like growth factors in immune regulation and tissue homeostasis during Graft versus Host (GvH) Disease
(Project Head
Zaiß, Dietmar M.W.
)
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INF - Data integration platform and systems medicine efforts to foster GvL and GvHD research
(Project Heads
Dandekar, Thomas
;
Holler, Ernst
;
Kehr, Birte
;
Kunz, Meik
)
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MGK - Integrated Research Training Group of the CRC/TRR 221
(Project Heads
Berberich-Siebelt, Friederike
;
Edinger, Matthias
;
Kremer, Anita
;
Walles, Heike
)
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Z01 - Pathology work-up of GvHD and GvL in mice and man
(Project Heads
Büttner-Herold, Maike
;
Evert, Matthias
;
Rosenwald, Andreas
)
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Z02 - Animal engineering and complex transplantation models
(Project Heads
Beilhack, Andreas
;
Hoffmann, Petra
;
Winkler, Thomas
)
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Z03 - Central tasks of the Collaborative Research Centre
(Project Head
Herr, Wolfgang
)
Completed projects