Mechanisms of action of extracorporeal photochemotherapy.

Extracorporeal photochemotherapy (ECP) has been shown to be effective in variety of pathologic diseases such as Sezary syndrome, autoimmune diseases, organ graft rejection and graft versus host disease. However, its mechanism of action has remained elusive. Understanding of its mechanisms may be useful to identify the best indications, treatment regimes and to optimize the ECP technique. The first step of the ECP procedure is collection of peripheral mononuclear cells. In this step, several cell environment changes occur. These conditions have been suggested to increase monocyte activation and possibly drive dendritic cell differentiation. The second step of ECP is the cell radiation by UVA in presence of 8-MOP which is presumed to induce cell membrane damage, DNA crosslinking and binding to a variety of cytosolic proteins leading to apoptosis, modification of membrane antigenicity and antigen presenting cell activation. The third step of ECP is the reinfusion of the treated cells to the patient. While it is unclear what exactly occurs in vivo, it is thought that DCs play a critical role by inducing an immunological response against pathogenic cells. The immature DC, activated by ECP, phagocytizes and internalizes the apoptotic cells; processes the antigens and increases the synthesis of class I and II Major Histocompatibility Complex (MHC) molecules. The peptides associated with class II MHC are presented to the CD4+ T helper cells. The final maturation of DC is completed in vivo with the help of these activated T helper cells using a variety of mechanisms including CD40 ligation. Finally, the mature DCs fully loaded with pathogenic T cell peptides migrate to secondary lymphoid organs stimulate the naive CD8+ T cells and induce a cytotoxic response (Th1 immune response) directed against pathogenic clones (tumoral cells of Sezary syndrome). Clinical and haematological improvement after ECP in Sezary syndrome is associated with a shift in Th1/Th2 balance and the increase of Th1 cytokines and IL12. ECP can also down regulate the allo or autoimmune response and induces tolerance by regulatory T cells. The clinical response to ECP in patients with chronic GvHD is associated with increase in NK cells and a shift from DC1 to DC2 and a shift from predominantly Th1 to Th2 immune response. Recruitment and involvement of other immune cells in the mechanism of ECP have been suggested and merit more studies. This immunostimulatory capacity of ECP is the most probable hypothesis of its mechanism but further investigations are necessary to determine the precise players important for this activity.