Studio della via di segnale PI3K/Akt/mTOR nelle Cellule Dendritiche

Allogeneic transplantation of hematopoietic stem cells (HTSC) is the most effective curative option for many neoplastic hematological disease. Acute graft versus host disease (aGVHD) is the most feared complication following HTSC and is caused by donor lymphocytes recognizing recipient histocompatibility antigen presented by antigen-presenting cells (APC). Removal or inactivation of APC before transplantation prevents GVHD. Nowadays there are no drugs specifically targeting APC. The molecular mechanisms involved in cell growth of these cells are well known and mostly involve the activation of the PI3K signaling pathway. In this study we tested the effects of two drugs targeting the PI3K pathway, rapamycin and perifosine on the differentiation of monocytes to distinct DC subtypes in vitro. Rapamycin decreased the recovery of monocyte-derived DC cultured in presence of IL-4 due to increased apoptosis, while monocytes cultured in GM-CSF with or without IFN-? were not affected. Rapamycin decreased the expression of the costimulatory molecules CD86 and increased the expression of CD1a in monocyte-derived DC, only in presence of IL-4. Moreover, rapamycin blocked the secretion of IL-12 and TNF-? and altered the allostimulatory capacity only in monocytes cultured with IL-4. Rapamycin didn't alter the survival and function of circulating DC. Treatment with perifosine was associated with increased apoptosis of monocytes cultured both with GM-CSF only or with GM-CSF and IL-4. Perifosine blocked the secretion of TNF-? by monocytes cultured with GM-CSF only and with GM-CSF and IL-4 after 3 days of culture. These results suggest that the action of rapamycin is more strictly dependent on IL-4 than perifosine, suggesting a possible use of perifosine in the prevention of GVHD before HSCT.