title: Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells.
abstract: Heme oxygenase-1 (HO-1) induction in, or carbon monoxide (CO), or bilirubin administration to, donors and/or recipients frequently lead to long-term survival (>100 days) of DBA/2 islets into B6AF1 recipients. We tested here whether similar treatments show value in a stronger immunogenetic combination, i.e., BALB/c to C57BL/6, and attempted to elucidate the mechanism accounting for tolerance. Induction of HO-1, administering CO or bilirubin to the donor, the islets or the recipient, prolonged islet allograft survival to different extents. Combining all the above treatments (the "combined" protocol) led to survival for >100 days and antigen-specific tolerance to 60% of the transplanted grafts. A high level of forkhead box P3 (Foxp3) and transforming growth factor beta (TGF-beta) expression was detected in the long-term surviving grafts. With the combined protocol, significantly more T regulatory cells (Tregs) were observed surrounding islets 7 days following transplantation. No prolongation of graft survival was observed using the combined protocol when CD4+ CD25+ T cells were predepleted from the recipients before transplantation. In conclusion, our combined protocol led to long-term survival and tolerance to islets in the BALB/c to C57BL/6 combination by promoting Foxp3+ Tregs; these cells played a critical role in the induction and maintenance of tolerance in the recipient.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215 USA.
authors.forename: Soo Sun
authors.initials: SS
authors.lastname: Lee
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.forename: Silvia
authors.initials: S
authors.lastname: Mazzola
authors.forename: Michael N
authors.initials: MN
authors.lastname: Thomas
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Bach
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin