CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of Indoleamine-2,3-dioxygenase.
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.
Pree
Ines
I
Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
Bigenzahn
Sinda
S
Fuchs
Dietmar
D
Koporc
Zvonimir
Z
Nierlich
Patrick
P
Winkler
Christiana
C
Brandacher
Gerald
G
Sykes
Megan
M
Muehlbacher
Ferdinand
F
Langer
Felix
F
Wekerle
Thomas
T
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
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000069594:Abatacept