- Dr. Cees van Kooten, Principal Investigator
- Leiden University Medical Center, Leiden, The Netherlands
- Survival Mechanisms of Human Dendritic Cells as a Tool to Direct Immune Response
Dendritic cells (DCs) serve as an essential link between innate and adaptive immune responses. They can induce both primary and secondary immune responses and are known to play key roles in immuno-stimulatory as well as immuno-suppressive responses. This dual function has made them potential targets in vaccine development for the prevention and treatment of infections and cancer as well as for the treatment and prevention of auto-immune diseases and allograft rejection. The longevity of DCs has been shown to be a critical factor influencing the outcome of immune responses.
The use of DC in clinical settings requires a thorough understanding of their survival mechanisms and the impact of altered DC longevity for cellular immune responses. Since, APCs comprise many different cell types, each with their own functional characteristics, this project is aimed at the identification and understanding of molecules and mechanisms that regulate the survival of different APCs with special interest in DC.
Recently, we have identified a survival pathway comprised of GM-CSF
->PI3K->mTOR->p27KIP1->Mcl-1 signaling, which is critical for monocyte-derived DC (MoDC), but not for monocytes or macrophages. Therefore, the specific aims of the present proposal are to identify the molecular mechanisms involved in moDC survival, to extrapolate these findings to a prolonged survival of murine DC and to improve allograft survival and tolerance induction. The identification of molecules that regulate the survival of distinct DC subsets will have an impact on the design of protocols aimed at inhibiting alloimmune reactivity or increase donor-specific tolerance in organ transplantation.