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TRR 221:  Modulation of graft-versus-host and graft-versus-leukemia immune responses after allogeneic stem cell transplantation

Subject Area Medicine
Term since 2018
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Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 324392634
 
Allogeneic hematopoietic stem cell transplantation (ASCT) 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 42 million voluntary stem cell donors are currently registered world-wide. The curative potential of ASCT is based on the replacement 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 ASCT offers a unique chance to rescue patients with otherwise incurable hematologic malignancies, still around one quarter of ASCT recipients develop disease relapse after ASCT. Thus, there is an urgent need to better understand and ultimately strengthen GvL responses. Yet, donor T cells also attack solid organs in about half of patients, 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 to elucidate the immunological mechanisms of GvL and GvHD responses to increase the efficacy of ASCT without increasing the risk for GvHD. To achieve this goal scientists of project area A analyze new molecular targets and cellular pathways (e.g. T cell receptor & chimeric antigen receptor transfer, T memory stem cells) to augment GvL responses and assess them in in vivo models. In project area B scientists examine 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 are and shall be tested in clinical trials. Several members of TRR are "clinician scientists" who continuously conduct first-in-man investigator-initiated clinical trials in the ASCT and cellular therapy field. Twenty-three trials are currently funded or applied for funding (from resources outside the TRR). Thus, TRR is strongly committed to bridge the gap between basic and translational immunology research in ASCT and cellular immunotherapy to achieve our fundamental mission: to improve the safety and efficacy of ASCT.
DFG Programme CRC/Transregios

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Applicant Institution Universität Regensburg
 
 

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