title: Prolongation of skin graft survival by exogenous ubiquitin.
abstract: Recently, it was shown that exogenous ubiquitin has anti-inflammatory actions in vivo and that the ubiquitin-decapeptide 50-59 has immunosuppressive effects similar to cyclosporine. Immunosuppressive effects of the native ubiquitin molecule and its therapeutic potential in transplantation are unknown. We tested the hypothesis that ubiquitin inhibits alloreactivity and increases allograft survival in a murine model of skin transplantation in fully mismatched strain combinations (C3H/HEJ-DBA2). Ubiquitin dose-dependently inhibited mixed leukocyte reaction in C3H/HEJ splenocytes in vitro. Intraperitoneal ubiquitin administration (25 microg/h for 14 days) was well-tolerated, dose-dependently increased ubiquitin serum concentrations and median allograft survival from 10 days (with albumin; control) to 17 days in DBA2 mice (survival ratio: 1.7, 95% confidence interval: 1.266-2.134; P=0.0005). The in vivo effects in this study combined with our previous work strongly indicate that ubiquitin is a potent immune modulator with broad therapeutic potential. Ubiquitin treatment could be a novel strategy to improve immunosuppressive regimens in transplantation.
authors.affiliation: DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Earle
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Haddad
authors.forename: Mayur B
authors.initials: MB
authors.lastname: Patel
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Si M
authors.initials: SM
authors.lastname: Pham
authors.forename: Matthias
authors.initials: M
authors.lastname: Majetschak
mesh_terms: D000818:Animals; D062109:Dermatologic Surgical Procedures; D006085:Graft Survival / Q000187:drug effects*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D012867:Skin / Q000187:drug effects*; D016038:Skin Transplantation; D025801:Ubiquitin / Q000008:administration & dosage* / Q000097:blood
chemical_list: D007166:Immunosuppressive Agents; D025801:Ubiquitin