Updating ECP action mechanisms

Extracorporeal Photochemotherapy (ECP) consists in illumination of the patient's leukocytes in the presence of 8-Methoxy Psoralen (8-MOP) and its reinjection to the same patient. ECP is responsible for many cellular events, the most important being the induction of cell apoptosis. Apoptosis appears first in lymphocytes and activated lymphocytes (allo or auto) which are more sensitive and undergo faster apoptosis rather than other cells. Monocytes develop apoptosis later. The injection of apoptotic cells induces tolerance in patients with graft versus host disease (GvHD) and acute heart or lung graft rejection. In these patients, phagocytosis of apoptotic cells by antigen-presenting cells (APCs) and in particular dendritic cells is responsible for a shift from Th1 to Th2 immune response, an increase in anti-inflammatory cytokines such as interleukine 10 (IL-10) and Tumor Growth Factor Beta (TGF-β), a decrease in pro-inflammatory cytokines and finally, for the proliferation of regulatory cells. Among CD4/CD25 positive cells, only CD4+CD25hi are T-regulatory cells (T-regs). One subpopulation of T-regs produces IL-10 and inhibits Th1 CD4 cells, whereas other populations act as suppressors and inhibit the cytotoxic T-cells responsible for organ rejection and GvHD in an antigen specific fashion. It is not clear why the injection of early apoptotic cells induces tolerance in GvHD and organ graft rejection, but in Sézary syndrome, it induces up-regulation of anti-tumor immune response. Immune response modulation (up- or down-regulation) after ECP depends on many factors: early apoptotic cell injection; anti-inflammatory environment; impaired function of dendritic cells; dendritic type 2 cell dominance, lead to immune tolerance, whereas late apoptotic or necrotic cell injection and pro-inflammatory cytokines enhance immune response. Therefore, immune response to ECP depends on various factors responsible for the diversity of its mode of action in different diseases and further investigations are required.