title: IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival.
abstract: Costimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig upregulates expression of the immunoregulatory enzyme IDO in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. In this study, we studied whether concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor-specific transfusion showed indefinite graft survival (>100 d) without signs of chronic rejection or donor specific Ab formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared with rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-dl-tryptophan, either at transplant or at postoperative day 50, abrogated CTLA4Ig + DST-induced long-term graft survival. Importantly, IDO1 knockout recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of regulatory T cells (Tregs) resulted in decreased IDO activity and again prevented CTLA4Ig + DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this costimulatory blocker.
authors: Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors: Robert
authors: R
authors: Sucher
authors: Klaus
authors: K
authors: Fischler
authors: Rupert
authors: R
authors: Oberhuber
authors: Irmgard
authors: I
authors: Kronberger
authors: Christian
authors: C
authors: Margreiter
authors: Robert
authors: R
authors: Ollinger
authors: Stefan
authors: S
authors: Schneeberger
authors: Dietmar
authors: D
authors: Fuchs
authors: Ernst R
authors: ER
authors: Werner
authors: Katrin
authors: K
authors: Watschinger
authors: Bettina
authors: B
authors: Zelger
authors: George
authors: G
authors: Tellides
authors: Nina
authors: N
authors: Pilat
authors: Johann
authors: J
authors: Pratschke
authors: Raimund
authors: R
authors: Margreiter
authors: Thomas
authors: T
authors: Wekerle
authors: Gerald
authors: G
authors: Brandacher
mesh_terms: D000069594:Abatacept; D000818:Animals; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000069594:Abatacept; D014364:Tryptophan