Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase.
Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 ± 0.3 μmol/mmol creatinine in the absence of acute GVHD, 8.0 ± 1.1 μmol/mmol creatinine for GVHD grade 1 or 2, and 13.5 ± 2.7 μmol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation.
Department of Haematology/Oncology, University Medical Center, Regensburg, Germany.
Karin
K
Landfried
Wentao
W
Zhu
Magdalena C
MC
Waldhier
Ute
U
Schulz
Julia
J
Ammer
Barbara
B
Holler
Daniel
D
Wolff
Matthias
M
Edinger
Katrin
K
Peter
Marina
M
Kreutz
Reinhard
R
Andreesen
Peter J
PJ
Oefner
Ernst
E
Holler
D000293:Adolescent; D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D015971:Gene Expression Regulation, Enzymologic; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology / Q000652:urine*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D007737:Kynurenine / Q000378:metabolism / Q000652:urine; D013058:Mass Spectrometry; D008875:Middle Aged; D017378:Quinolinic Acid / Q000378:metabolism / Q000652:urine; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013997:Time Factors; D014184:Transplantation, Homologous; D014364:Tryptophan / Q000378:metabolism / Q000652:urine*; D055815:Young Adult
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid