La photochimiothérapie extra-corporelle.

Abstract

La photochimiotherapie extracorporelle (PCE) consiste en une manipulation ex vivo de cellules humaines. Les cellules mononucleees du malade sont prelevees, traitees ex vivo par 8-methoxypsoralene et irradiation UVA, avant d 'etre reinjectees. Cette technique implique la maitrise de differents parametres qui incluent l' obtention de leucocytes, une concentration de psoralene et une irradiation UVA optimales. Les cibles moleculaires de la PCE se situent au niveau membranaire, cytoplasmique et nucleaire. L' effet therapeutique semble reposer sur la conjonction de plusieurs effets biologiques et trois hypotheses principales ont ete proposees : (1) inhibition de la proliferation cellulaire et photodestruction cellulaire par apoptose par effet direct sur le genome; (2) production de cytokines immunomodulatrices par induction d' une transcription genique; (3) effets immunologiques cellulaires. Plusieurs modeles experimentaux chez l' animal ont confirme l' immunomodulation induite in vivo par la PCE et ont motive son utilisation chez l' homme pour le traitement de diverses affections caracterisees par une proliferation anarchique de certains clones lymphocytaires T benins ou malins. Sa place en therapeutique humaine n' est toutefois pas encore definie et l' efficacite therapeutique de cette technique reste a demontrer.

Extracorporeal photochemotherapy (ECP) is a therapeutic procedure which combines leukapheresis and PUVAtherapy (psoralen plus UVA radiation). This novel form of cell therapy consists of collection of mononuclear cells and their irradiation with UVA in the presence of a photoactivable molecule (8-methoxypsoralen), before being reinfused. ECP was developed to induce a modulation of immune response similar to that observed after in vivo phototherapy. The photophoresis procedure requires three steps including white blood cells collection, and the precise control of psoralen concentration and UVA dose. Advantages and inconvenients of the two ECP procedures available for human use are respectively discussed. Mechanisms of action of ECP are currently incompletely defined and different hypotheses are suggested. On the molecular level, DNA, cell membrane, and cytoplasm are involved in the biologic effects of EPC. The therapeutic effect of ECP is likely induced by the combination of different bi ological consequences and 3 main hypotheses have been suggested: (1) inhibition of cell proliferation and cell photodestruction by apoptosis caused by a direct effect on DNA; (2) production of immunomodulatory cytokines induced by gene transcription; (3) immunological effects such as EPC-induced increase of the MHC class I and II expression (which are involved in the antigen presentation), and the generation of specific suppressor T lymphocytes CD8+. These immunological alterations may lead to the elimination of the pathogenic T cells. Different experimental animal models have confirmed the in vivo modulation of immune response by ECP and have stimulated its use for human treatment of diseases involving benign or malignant clonal T cell proliferation (cutaneous T-cell lymphoma, autoimmune diseases, graft - versus - host disease, allograft rejection). Although ECP appears to be a safe and well tolerated form of cell therapy, its potential indications remain to be further demonstrated b y clinical controlled trials.