Novel pharmacological approaches to separate GVHD from GVL reactions by differential modulation of T cell and DC effector functions
Project management at the University of Würzburg:
Graft versus host disease (GVHD) is a severe complication after allogeneic hematopietic stem cell transplantation (HSCT), which leads to a state of immunodeficiency. This immunodeficiency is aggravated by current therapeutic approaches. The separation of GVHD from the beneficial graft versus leukemia (GVL) effects is thus far insufficient. Tyrosine kinase inhibitors (TKIs) are applied in the frame of allogeneic HSCT without evidence for an increase in transplantation associated mortality. First clinical data indicate that TKIs may hamper GVHD. An enhancement of anti-leukemic effects has been observed under a monotherapy with the TKI dasatinib in case of concurrent large granular lymphocyte (LGL) expansion. Thus far, it has not been systematically analysed how these effects may be inducable in a rational and controlled fashion. Aim of this project is to determine the underlying mechanisms of action for these observations to enable a controlled inhibition of GVHD and enhancement of GVL effects. A successful separation of GVHD from GVL effects should reduce morbidity and mortality and thus help to improve the results of an allogeneic HSCT. Therefore, we will analyse the effects of TKIs on the interaction of T cells with dendritic cells relevant for GVHD and GVL reactions and further evaluate a differential modulation of leukemic specific vs. allo specific T cell clones by TKIs. Functional assays, Western Blot, RT-PCR, siRNA technology and gene expression analysis will be performed to reach this aim.
Projekt period: from 01.2010 to 12.2011
Sonstige öffentliche Mittel ( Wilhelm-Sander-Stiftung ) ,Granting date: 24.11.2009