Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase

Abstract

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.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation

“…1 We measured IDO activity in the patient sera as a possible marker for tolerogenic DCs, 9 and found an upregulation in patients with cGvHD consistent with previous findings in acute GvHD 25 but not previously shown in cGvHD. This probably reflects an adequate but insufficient upregulation of immunosuppressive mechanisms in response to an inflammatory milieu.…”

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

“…*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Bonferroni's multiple comparisons post test (A and B) and unpaired Student's t test (C-E). (Eppendorf) using a QuantiFast SYBR Green PCR Kit (QIAGEN) according to the manufacturers' instructions and as previously described (45).…”

CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs

“…18 Cytokine measurements IFN-g was quantified in supernatants using an IFN-g ELISA (R&D Systems, Minneapolis, MN), IL-1b, IL-6, IL-10, granulocyte macrophage-CSF, and TNFa using an Inflammatory Cytokine Multi-Analyte ELISArray kits (Qiagen, Hilden, Germany). For personal use only.…”