Effects of SRC kinase inhibitors on antigen specific T-cell-activation and proliferation
Project management at the University of Würzburg:
Tyrosine kinase (TK) inhibitors such as imatinib (Glivec?) have entered the clinic as specific cancer treatments. Imatinib is now first-line therapy for chronic myeloid leukemia (CML) and is increasingly used in conjunction with allogeneic hematopoietic stem cell transplantation (HSCT). Little is known about its impact on graft versus host disease (GVHD), graft versus leukemia (GVL), or other immune-mediated processes impacting on transplant outcome. We and others have found that imatinib has T-cell suppressive effects in vitro, possibly via LCK inhibition. Clinical results are contradictory. Patients can become resistant to imatinib, thus there is a demand for alternative kinase inhibitors. Several TK inhibitors are currently undergoing pre-clinical or clinical development. However, while these agents show much promise, there are concerns that concurrent immunosuppressive effects mediated through inhibition of TKs involved in antigen receptor signaling pathways might diminish their benefit/risk ratio. The overall aim of this proposal is to conduct a detailed investigation of the immunobiological effects of clinically relevant TK inhibitors, such as BMS-354825. In particular, this work will determine the impact of TK inhibitors on antigen-specific T-cell responses to intracellular pathogens, especially chronic persistent viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), and leukemia-reactive T-cell responses. CD8+ T cell-mediated immunity is essential for long-term control of persistent DNA viruses. Immunosuppression can lead to recrudescence and consequent disease manifestations, while leukemia-reactive CD8+ T-cell responses are thought to be crucial for graft-versus leukemia (GVL) effect after HSCT. Advanced immuntechnological approaches to these issues will provide basic mechanistic data that might aid in rational use of these drugs in allogeneic stem cell transplantation and potentially lead to the development of novel immunosuppressants.
Projekt period: from 05.2006 to 05.2008
DFG ,Granting date: 06.04.2006