title: Melatonin in vivo prolongs cardiac allograft survival in rats.
abstract: Melatonin, secreted by the pineal gland, is a multifunctional agent which (i) protects tissues from damage through free radical scavenging and attenuates ischemia/reperfusion injury in organ grafts; (ii) acts synergistically with cellular antioxidants; and (iii) displays complex, dose-dependent immunoenhancing and suppressing effects in vitro and in vivo. We analyzed the immunomodulatory effect of melatonin on acute allograft rejection. Cardiac grafts were transplanted from LBNF1 to LEW rats and anastomosed to the abdominal great vessels. The effect of low-dose (LD; 20 mg/kg/day) and high-dose (HD; 200 mg/kg/day) melatonin treatment in recipients compared with untreated controls was investigated. HD melatonin therapy abrogated acute rejection, significantly prolonging allograft survival (mean survival: 12.3 +/- 1 days S.D., n = 8, P < 0.0001) compared with untreated controls, which rapidly reject the transplant (6.3 +/- 1 days n = 12). LD therapy did not extend survival significantly (7.3 +/- 1.1 days, n = 12). Allospecific IgM showed a significant decrease in animals receiving HD therapy versus untreated recipients at days 10 and 14 post-transplantation (P < 0.01), whereas in the LD group at day 10, a significant increase in allospecific IgM (P < 0.01) over the HD cohort was demonstrated. HD treatment markedly reduced lymphocyte proliferative capacity compared with controls and the LD group. HD melatonin treatment abrogated acute allograft rejection and significantly prolonged graft survival. Our results suggest an involvement of melatonin in humoral and cellular immune pathways following perfused organ transplantation. These findings may indicate a novel therapeutic approach, based on modulation of the neuroendocrine/immune axis through melatonin as a possible future immunosuppressant in organ transplantation.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Jung
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Luc
authors.initials: L
authors.lastname: Härter
authors.forename: Ilhan
authors.initials: I
authors.lastname: Inci
authors.forename: Didier
authors.initials: D
authors.lastname: Schneiter
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.forename: Marius
authors.initials: M
authors.lastname: Keel
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Stephan
authors.initials: S
authors.lastname: Korom
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000502:physiology; D010870:Pineal Gland / Q000502:physiology; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000975:Antioxidants; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D008550:Melatonin