Psoralen and UVA light: an in vitro investigation of multiple immunological mechanisms underlying the immunosuppression induction in allograft rejection.
Photopheresis (ECP) is a novel immunomodulatory therapy effectively used to treat several T-cell-mediated diseases and to reverse allograft rejection after organ transplantation. It consists of infusion of UVA-irradiated autologous leukocytes collected by apheresis and extracorporeally incubated with 8-methoxypsoralen (8-MOP). In this study we explored the potential immunological events for therapeutic efficacy of photopheresis in preventing allograft rejection by evaluating in vitro the combined effects of 8-MOP and UVA (PUVA) on multiple immunological parameters, such as induction of apoptosis, production of soluble mediators, and expression of cell antigens. Peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects were treated with 8-MOP and UVA at the same doses as those clinically used in ECP. We demonstrate that PUVA treatment induced leukocyte hyporesponsiveness and a decrease in expression of co-stimulatory and adhesion molecules as well as of cytokine levels. Additionally, PUVA treatment induced apoptosis in both mononuclear cells (possibly through the Fas/FasL system and/or the CD38 pathway) and purified monocytes. In conclusion, our work focuses attention on the initial phase of immune response and identifies some new targets of therapy (e.g., costimulatory molecules) able to trigger final effects underlying therapeutic efficacy of photopheresis.
Legitimo
A
A
Department of Pediatrics, Laboratory of Immunology, University of Pisa, Via Roma 67, 56100 Pisa, Italy.
Consolini
R
R
Di Stefano
R
R
Bencivelli
W
W
Mosca
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002648:Child; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005363:Ficusin / Q000494:pharmacology; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control / Q000532:radiotherapy; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000528:radiation effects*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000528:radiation effects; D008730:Methoxsalen / Q000494:pharmacology*; D008875:Middle Aged; D017893:Photopheresis; D017319:Photosensitizing Agents / Q000494:pharmacology; D023001:Transplantation Tolerance / Q000187:drug effects / Q000528:radiation effects; D014184:Transplantation, Homologous; D014466:Ultraviolet Rays
D016207:Cytokines; D017319:Photosensitizing Agents; D005363:Ficusin; D008730:Methoxsalen