title: Bilirubin can induce tolerance to islet allografts.
abstract: Induction of heme oxygenase-1 (HO-1) expression in recipients of allogeneic islets can lead to long-term survival (>100 d) of those islets. We tested whether administration of bilirubin would substitute for the beneficial effects of HO-1 expression in islet transplantation. Administering bilirubin to the recipient (B6AF1) or incubating islets in a bilirubin-containing solution ex vivo led to long-term survival of allogeneic islets in a significant percentage of cases. In addition, administering bilirubin to only the donor frequently led to long-term survival of DBA/2 islets in B6AF1 recipients and significantly prolonged graft survival of BALB/c islets in C57BL/6 recipients. Donor treatment with bilirubin up-regulated mRNA expression of protective genes such as HO-1 and bcl-2 and suppressed proinflammatory and proapoptotic genes including monocyte chemoattractant protein-1 and caspase-3 and -8 in the islet grafts before transplantation. Furthermore, treatment of only the donor suppressed the expression of proinflammatory cytokines including TNF-alpha, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and other proapoptotic and proinflammatory genes normally seen in the islets after transplantation. Donor treatment also reduced the number of macrophages that infiltrated the islet grafts in the recipients. Preincubation of betaTC3 cells with bilirubin also protected the cells from lipid peroxidation. Our data suggests that the potent antioxidant and antiinflammatory actions of bilirubin may contribute to islet survival.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA, hwang3@bidmc.harvard.edu
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.forename: Soo Sun
authors.initials: SS
authors.lastname: Lee
authors.forename: Carlotta
authors.initials: C
authors.lastname: Dell'Agnello
authors.forename: Vaja
authors.initials: V
authors.lastname: Tchipashvili
authors.forename: Joana Costa Pinto
authors.initials: JC
authors.lastname: d'Avila
authors.forename: Joanna
authors.initials: J
authors.lastname: D'Avilla
authors.forename: Eva
authors.initials: E
authors.lastname: Czismadia
authors.forename: Beek Yoke
authors.initials: BY
authors.lastname: Chin
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Bach
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000601:surgery; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013045:Species Specificity; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D001663:Bilirubin