title: Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation.
abstract: The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-gamma (IFN-gamma) and via tryptophan depletion, suppresses adaptive T cell-mediated immunity in inflammation, host immune defense, and maternal tolerance. Its role in solid organ transplantation is still unclear. Therefore, we investigated the usefulness of IDO-mediated tryptophan catabolism in the evaluation of kidney allograft rejection. Blood, urine, and tissue samples were collected from 34 renal transplant patients without rejection and from nine patients with biopsy-confirmed episodes of acute rejection (n=12). Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography. Kynurenine to tryptophan ratio (kyn/trp) was calculated to estimate IDO activity. Immunostaining for IDO was performed on renal biopsies. Neopterin was assessed using radioimmunoassay. Kyn/trp and neopterin were detectable at low levels in serum of healthy volunteers and were increased in non-rejecting allograft recipients. Serum levels of kyn/trp were higher in recipients with rejection compared to non-rejectors as early as by day 1 post-surgery. Rejection episodes occurring within 13+/-5.9 days after transplantation were accompanied by elevated kyn/trp in serum (114+/-44.5 micromol/mmol, P=0.001) and urine (126+/-65.9 micromol/mmol, P=0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-gamma-induced increase in IDO activity. Immunostaining showed upregulation of IDO in rejection biopsies, localized in tubular-epithelial cells. Non-rejected grafts displayed no IDO expression. Acute rejection is associated with simultaneously increased serum and urinary kyn/trp in patients after kidney transplantation. Thus, IDO activity might offer a novel non-invasive means of immunomonitoring of renal allografts.
authors.affiliation: Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria. gerald.brandacher@uibk.ac.at
authors.forename: G
authors.initials: G
authors.lastname: Brandacher
authors.forename: F
authors.initials: F
authors.lastname: Cakar
authors.forename: C
authors.initials: C
authors.lastname: Winkler
authors.forename: S
authors.initials: S
authors.lastname: Schneeberger
authors.forename: P
authors.initials: P
authors.lastname: Obrist
authors.forename: C
authors.initials: C
authors.lastname: Bösmüller
authors.forename: G
authors.initials: G
authors.lastname: Werner-Felmayer
authors.forename: E R
authors.initials: ER
authors.lastname: Werner
authors.forename: H
authors.initials: H
authors.lastname: Bonatti
authors.forename: R
authors.initials: R
authors.lastname: Margreiter
authors.forename: D
authors.initials: D
authors.lastname: Fuchs
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D003404:Creatinine / Q000097:blood; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology / Q000502:physiology*; D007737:Kynurenine / Q000097:blood; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D014364:Tryptophan / Q000097:blood
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D019798:Neopterin; D014364:Tryptophan; D003404:Creatinine