title: CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of Indoleamine-2,3-dioxygenase.
abstract: Bone marrow transplantation (BMT) under costimulation blockade induces mixed chimerism and tolerance in rodent models. Recent data, predominantly from in vitro studies, suggest that in addition to blocking the CD28 costimulation pathway CTLA4Ig also acts through upregulating the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). Here we demonstrate that even though CTLA4Ig is critically required for the induction of chimerism and tolerance in a murine model of nonmyeloablative BMT, IDO activity is not. No significant differences were detectable in the kynurenine to tryptophan ratios (indicative of IDO activity) in sera of BMT recipients treated with CTLA4Ig (tolerant group) versus BMT recipients treated without CTLA4Ig (nontolerant group) versus naïve controls. In vivo inhibition of IDO immediately after BMT with CTLA4Ig or several months thereafter did not block achievement of chimerism and tolerance. Thus, IDO does not play a critical role in the induction or maintenance of chimerism and tolerance in a CTLA4Ig-based BMT model.
authors.affiliation: Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Pree
authors.forename: Sinda
authors.initials: S
authors.lastname: Bigenzahn
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Koporc
authors.forename: Patrick
authors.initials: P
authors.lastname: Nierlich
authors.forename: Christiana
authors.initials: C
authors.lastname: Winkler
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Muehlbacher
authors.forename: Felix
authors.initials: F
authors.lastname: Langer
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000069594:Abatacept; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000069594:Abatacept