Indoleamine 2,3-dioxygenase in lung allograft tolerance.
BACKGROUND
Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the degradation of tryptophan (Try) to kynurenine (Kyn), is thought to suppress T-cell activity. Although a few experimental studies have suggested a role for IDO in graft acceptance, human data are scarce and inconclusive. We sought to establish whether, in lung transplant recipients (LTRs), plasma IDO activity mirrors the level of graft acceptance.


METHODS
We measured the plasma Kyn/Try ratio, reflecting IDO activity, by high-performance liquid chromatography (HPLC) in 90 LTRs, including 26 patients who were still functionally/clinically stable for >36 post-transplant months (stable LTRs) and 64 LTRs with bronchiolitis obliterans syndrome (BOS, Grades 0-p to 3). Twenty-four normal healthy controls (NHCs) were also included.


RESULTS
The Kyn/Try ratio in stable LTRs resembled that observed in NHCs, whereas, unexpectedly, patients with BOS, who had lower counts of peripheral CD4(+) T-regulatory cells and tolerogenic plasmacytoid dendritic cells than stable LTRs, showed an increased plasma Kyn/Try ratio compared with both NHCs and stable LTRs. IDO expression by in vitro-stimulated peripheral blood mononuclear cells (PBMC) did not vary between BOS and stable LTRs. Furthermore, BOS patients displayed signs of chronic systemic inflammation (increased plasma levels of interleukin-8 and tumor necrosis factor-alpha) and higher T-cell activation (increased frequency of peripheral interferon-gamma-producing clones).


CONCLUSIONS
Our results suggest that, in vivo, in lung transplantation, plasma IDO activity does not reflect the degree of lung graft acceptance, but instead is correlated with the degree of chronic inflammation.
Department of Haematological, Pneumological and Cardiovascular Sciences, Section of Pneumology, University of Pavia and IRCCS San Matteo Foundation, Via Taramelli 5, Pavia, Italy. f.meloni@smatteo.pv.it
Federica
F
Meloni
Serena
S
Giuliano
Nadia
N
Solari
Paola
P
Draghi
Simona
S
Miserere
Anna Maria
AM
Bardoni
Roberta
R
Salvini
Francesco
F
Bini
Anna Maria
AM
Fietta
D015415:Biomarkers / Q000097:blood; D001989:Bronchiolitis Obliterans / Q000097:blood / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood; D007737:Kynurenine / Q000097:blood; D016040:Lung Transplantation / Q000502:physiology*; D011183:Postoperative Complications / Q000097:blood / Q000201:enzymology; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000201:enzymology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000502:physiology*; D014184:Transplantation, Homologous / Q000502:physiology*; D014364:Tryptophan / Q000097:blood
D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016209:Interleukin-8; D007737:Kynurenine; D014364:Tryptophan