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Prevention of acute Graft-versus-Host Disease after allogeneic Stem Cell Transplantation by molecular targeting of anti-apoptotic proteins in activated donor T cells

Graft-versus-Host-Disease (GvHD) is the most frequent severe complication in allogeneic stem cell transplantation (SCT) and to a large extent contributes to non-relapse mortality. GvHD results from an aggressive immune response of donor-derived allo-reactive T cells directed against host tissues. Recently it has been shown that high-dose, post-transplantation Cyclophosphamide (ptCy) is an effective strategy for GvHD prevention even in HLA-mismatched T cell replete SCT. It is assumed that the selective killing of proliferating, allo-reactive T cells is the main and dominant mechanism. Although ptCy is a rather unspecific and quite toxic regimen this approach opens the opportunity to study molecular mechanisms of GvHD induction and prevention.
In this research proposal we want to take up the hypothesis that targeting of anti-apoptotic BCL-2 family members in donor T cells activated by allo-stimulation provides a specific and effective strategy to prevent GvHD. We will analyze the expression-kinetics of anti- and pro-apoptotic mitochondrial proteins in T cells upon allo-stimulation both in allo-specific transgenic T cell receptor-bearing and in wildtype T cells in vitro. Based on the expression kinetics of individual anti-apoptotic molecules we will test their function and potential as therapeutic targets to prevent GvHD. We will target individual anti-apoptotic genes in vitro with various approaches including BH3-mimetics and/or BH3-peptides of pro-apoptotic proteins, gene-specific stable RNAi upon lentiviral gene transfer, knockout cells, and CRISPR/Cas9 technology, respectively. Based on the in vitro results we will evaluate anti-apoptotic candidates in vivo in a murine model of acute GvHD (BH3-mimetics, stable RNAi, knock-out T cells, CRISPR/Cas9). In parallel we will test in an in vivo model whether this early and targeted anti-GvHD intervention affects graft-versus-tumor effects (GvT), which are indispensable for treatment success of SCT to treat malignant diseases.


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