TY - JOUR
T1 - Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation
AU - Brandacher, G.
AU - Cakar, F.
AU - Winkler, C.
AU - Schneeberger, S.
AU - Obrist, P.
AU - Bösmüller, C.
AU - Werner-Felmayer, G.
AU - Werner, E. R.
AU - Bonatti, H.
AU - Margreiter, R.
AU - Fuchs, D.
N1 - Funding Information:
The authors thank Astrid Haara and Petra Höfler for excellent technical assistance. This work was supported by the Austrian Federal Ministry of Social Affairs and Generations, Ludwig Boltzmann Gesellschaft, Vienna, Austria, and Fonds zur Förderung der Wissenschaftlichen Forschung (FWF), Project No. 16059 (to GWF) and 16188 (to ERW).
PY - 2007/1
Y1 - 2007/1
N2 - The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-γ (IFN-γ) 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 μmol/mmol, P=0.001) and urine (126±65.9 μmol/mmol, P=0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-γ-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.
AB - The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-γ (IFN-γ) 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 μmol/mmol, P=0.001) and urine (126±65.9 μmol/mmol, P=0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-γ-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.
KW - Acute allograft rejection
KW - Renal transplantation
KW - Tolerance
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U2 - 10.1038/sj.ki.5002023
DO - 10.1038/sj.ki.5002023
M3 - Article
C2 - 17136028
AN - SCOPUS:33845694341
SN - 0085-2538
VL - 71
SP - 60
EP - 67
JO - Kidney international
JF - Kidney international
IS - 1
ER -