Plasma Indoleamine 2,3-dioxygenase Research Articles

Tryptophan and Its Derived Metabolites as Biomarkers for Tuberculosis Disease: A Systematic Review

Feasible diagnostic assays are required to detect new tuberculosis (TB) cases and monitor treatment. This study aimed to evaluate evidence on tryptophan (Trp) and its metabolites as proposed biomarkers for TB. Through specific keyword searches, we identified 170 relevant literature sources and included seven publications (from 2013 to 2023). The biomarker used in these studies were indoleamine 2, 3-dioxygenase (IDO) activity, IDO-1 gene expression, and plasma IDO protein, measured using ELISA, liquid chromatography-mass spectrometry, ultraperformance liquid chromatography mass spectrometry, and transcriptional profiling. The studies encompassed a pediatric case-control and six studies involving adults, pregnant women with TB-HIV, and individuals with multidrug-resistant tuberculosis, active TB, and latent TB. The assessment of IDO activity and IDO protein level demonstrated promising performance in distinguishing active TB from controls and in evaluating treatment failure and recurrent cases to controls. Trp and its metabolites fulfilled nearly all of target product profile criteria for detecting active TB. This study highlights the potential of utilizing host Trp and its metabolites as non-sputum-based biomarker for TB infection.

Prediction Model for Early-Stage CKD Using the Naples Prognostic Score and Plasma Indoleamine 2,3-dioxygenase Activity.

Changes in inflammation, immunity, and nutritional status can promote the development of chronic kidney disease (CKD), and the Naples prognostic score (NPS) reflects changes in these three general clinical parameters. Indoleamine 2.3-dioxygenase (IDO) can block the function of inflammatory cells and inhibit the production of inflammatory cytokines. We examined use of the NPS and IDO activity to predict early-stage CKD. Clinical and demographic parameters and the NPS were recorded for 47 CKD patients and 30 healthy controls. A one-way ANOVA or the rank sum test was used to compare variables in the different groups. Spearman or Pearson correlation coefficients were calculated, and logistic regression was used to identify significant factors. Receiver operating characteristic (ROC) analysis was also performed. The NPS had a positive correlation with plasma IDO activity and IDO activity was lowest in controls, and increased with CKD stage. ROC analysis indicated that NPS had an area under the curve (AUC) of 0.779 when comparing controls with all CKD patients. A prediction model for CKD (-4.847 + [1.234 × NPS] + [6.160 × plasma IDO activity]) demonstrated significant differences between controls and patients with early-stage CKD, and for patients with different stages of CKD. This model had AUC values of 0.885 (control vs CKD1-4), 0.876 (control vs CKD2), 0.818 (CKD2 vs CKD3), and 0.758 (CKD3 vs CKD4). A prediction model based on the NPS and IDO provided good to excellent predictions of early-stage CKD.

Perioperative IDO-1 dynamic changes in NSCLC patients.

e20532 Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that is involved in the metabolism of tryptophan, an essential amino acid. It is known to play a role in the regulation of the immune system, and has been linked to perioperative immune status. Specifically, IDO has been shown to be upregulated in the perioperative period, leading to an increased risk of infection and other complications. This is thought to be due to the increased production of kynurenine, a metabolite of tryptophan, which has been associated with immunosuppression. Additionally, IDO has been linked to increased levels of inflammation and oxidative stress, which can further contribute to the risk of complications during surgery. Thus, understanding the role and dynamic changes of IDO in the perioperative period is important for optimizing patient outcomes. Methods: Patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study prospectively. Peripheral blood at different time points: preoperative, post anesthesia, post-vascular incision, post-tumor resection, and 3 days after surgery. The serum tryptophan and kynurenine were measured, and the kynurenine to tryptophan (K:T) ratio was used as an indicator of IDO activity. Paired Wilcoxon test was used to identify the significant difference of IDO activity at five different time points. The Kaplan–Meier log-rank test was used to assess the correlation between overall survival (OS), progression-free survival (PFS), and IDO activity. Results: A total of 46 patients were enrolled in this study. The median follow-up time was 24.7 (range: 0.9 – 35.3) months. No patients died during the follow-up time. The PFS at 2 years was 76% (95% CI, 76%-100%). In all patients, IDO activity was not correlated significantly with better PFS. Surgical procedure does not affect levels of plasma IDO at any pathological stage in NSCLC significantly. The level of serum IDO of post-vascular incision was significantly correlated with that of 3 days after surgery (R2 = 0.7, P < 0.05). The level of preoperative level of serum kynurenine was significantly correlated with that of post-vascular incision and post-tumor resection (R2 = 0.7/0.73, P < 0.05). Conclusions: Surgical procedure does not have a significant effect on the serum IDO levels during the perioperative period. The perioperative levels of serum IDO are not correlated with the surgical prognosis of NSCLC, thus alternative markers are needed to better predict the surgical prognosis of NSCLC patients.

Plasma and Urine Indoleamine 2,3-Dioxygenase Activity: Promising Biomarkers for Chronic Kidney Disease and Inflammation Status.

PurposeOur aim was to determine the relationship between plasma and urine indoleamine 2.3-dioxygenase (IDO) activity and stage of chronic kidney disease (CKD).Patients and MethodsDemographic and clinical parameters, including plasma and urine IDO activity, were recorded in 47 CKD patients and 30 controls. One-way ANOVA with the least significant difference method was used to compare means of variables that had normal distributions and homogeneous variance. Variables with non-normal distributions were log-transformed and compared using the rank sum test Pearson or Spearman correlation coefficients were determined. Binary logistic regression and ordinal logistic regression were used to identify independently significant factors. Receiver operating characteristic (ROC) analysis was performed.ResultsThe control group had higher levels of hemoglobin and albumin and lower levels of creatinine and blood urea nitrogen (BUN; all P<0.01). The level of highly sensitive C reactive protein (hs-CRP) increased as CKD stage increased (P<0.01). Plasma and urine IDO activity were positively correlated (r=0.7, P<0.01). Plasma IDO activity correlated with age, creatinine, BUN, triglycerides, uric acid, albumin, and hemoglobin (all P<0.05); urine IDO activity correlated with age, BMI, creatinine, BUN, and hemoglobin (all P< 0.05). There were positive correlations of hs-CRP level with plasma IDO activity and urine IDO activity (both P<0.01). After adjusting for CKD-related factors, plasma IDO activity, urine IDO activity, and hs-CRP were independent risk factors for CKD (all P<0.05). Ordinal logistic regression also indicated that plasma and urine IDO activity were significantly associated with CKD stage. ROC analysis indicated that plasma and urine IDO activity were good predictors of CKD and distinguished different stages of CKD. There was a strong correlation between plasma IDO activity and inflammatory status in patients with CKD (OR=1258.908, P<0.01).ConclusionPlasma and urine IDO activity have potential use as biomarkers for early-stage CKD, progression of CKD, and inflammation status.

IDO Immune Status After Radiotherapy in Patients With IV Stage Non-Small Cell Lung Cancer: An Exploratory Study

<h3>Purpose/Objective(s)</h3> Host immunity has a significant impact on radiotherapy (RT) outcomes in cancer. We have previously demonstrated that Indoleamine 2, 3-dioxygenase (IDO), a known immunoinhibitory kinase, predicts the survival of patients with stage I/II after RT alone and stage III non-small cell lung cancer (NSCLC) after chemoradiation. We hypothesize that the IDO activity levels in the blood also change in patients with stage IV NSCLC following radiotherapy. <h3>Materials/Methods</h3> This was part of a prospective study of circulating immune biomarkers for prognosis and prediction. Newly diagnosed or recurrent stage IV NSCLC patients were eligible. Blood samples were obtained before and after RT start and platelet-poor plasma samples were used for the kynurenine (Kyn) and tryptophan (Trp) measurement by high-performance liquid chromatography. Kyn and Trp was detected on a UV/vis channel at 360 nm and 285 nm, respectively, with more than 95% re-productivity. IDO activity was defined as the ratio between Kyn and Trp in synchronization. Student T-test was applied for group comparison. Data are presented as mean and 95% confidence interval (CI). <i>P</i> value < 0.05 was considered as statistical significance. <h3>Results</h3> Between July 2019 and Dec 2020, a total of 54 patients with stage IV NSCLC treated with radiotherapy was recruited. RT dose ranged from 20-60 Gray in 5-30 fractions, covering thoracic, spines or brain. Higher concentration of Kyn (mean = 1.88, CI = 1.48-2.27 mM) was detected before RT, compared with the Kyn concentration (mean = 1.20, CI = 0.70-1.70 mM) after RT (<i>P</i> = 0.052). The mean concentration of Trp was 20.81 (CI = 17.01-24.62) mM before RT, compared with 19.01 (CI = 17.03-21.00) mM after RT with no significant change (<i>P</i> = 0.982). In addition, the IDO activity (mean = 0.11, CI = 0.08-0.14) before RT was higher than the IDO activity after RT (mean = 0.08, CI = 0.05-0.10) with <i>P</i> = 0.130. Furthermore, a subgroup analysis of the IDO activity in patients with distant metastasis (n = 31) was conducted. The mean concentration of Kyn was significantly decreased from 1.78 (CI = 1.67-2.67) mM before RT to 0.68 (CI = 0.28-2.09) mM after RT (<i>P</i> = 0.028). The mean concentration of Trp was 18.12 (CI = 15.39-20.84) mM before RT versus 18.64 (CI = 14.41-22.86) mM after RT (<i>P</i> = 0.847). Besides, the IDO activity was also reduced from 0.15 (CI = 0.09-0.20) before RT to 0.07 (CI = 0.01-0.13) after RT (<i>P</i> = 0.051). <h3>Conclusion</h3> This study reveals that the plasma kynurenine and IDO activity is reduced after RT, suggesting that potential roles of RT in releasing immune suppression status of the host that can be simply tested by IDO activity in patients with stage IV NSCLC.

Plasma indoleamine 2,3-dioxygenase, a highly sensitive blood-based screening tool for active tuberculosis disease in HIV-infected pregnant women

Background: The World Health Organization has identified the need for a non-sputum-based test capable of detecting active tuberculosis (TB) as a key TB control intervention. Indoleamine 2,3-dioxygenase (IDO) is an enzyme, which converts tryptophan to kynurenines. Recently, IDO activity has been proposed as a blood-based TB biomarker. We investigated whether plasma IDO activity, as measured by kynurenine-to-tryptophan ratio, could be used to screen HIV-infected pregnant women for active TB disease. Methods and materials: Using a commercial enzyme-linked immunosorbent assay (ELISA), we measured plasma tryptophan and kynurenine concentration to determine IDO activity in 78 HIV-infected pregnant women with active TB disease. We compared HIV-infected active TB cases to 120 control subjects from the same cohort with no TB, matched by age, and gestational age. Results: Plasma IDO activity was significantly elevated during pregnancy than in non-pregnant state, and increased transiently during labour (P < 0.0001). There was, however, a marked elevation of IDO activity in TB patients at the time of TB diagnosis (enrolment time-point) compared to pregnant women with no-TB (P < 0.0001). Using a previously determined cut-off of 0.080 in non-pregnant subjects, IDO activity showed a sensitivity of 97% (CI 91–99), specificity of 81% (CI 77–84), PPV 66% and NPV of 99% at the time of TB diagnosis. A receiver operating characteristic curve (ROC) gave area under curve of 0.96 (CI 95–98, P value < 0.0001). The optimal cut-off in pregnant women, however, was calculated as 0.10 with sensitivity of 96% (CI 89–99), specificity of 90% (CI 87–92), PPV 73% and NPV 99%. Conclusion: Plasma IDO activity is a sensitive blood-based screening test for TB in pregnant women living HIV. IDO activity can be measured using ELISA. IDO activity should be used to screen pregnant women at risk active TB disease.

Mycobacterium tuberculosis co-infection is associated with increased surrogate marker of the HIV reservoir

BackgroundTuberculosis (Tb) is the most frequent opportunistic infection among people living with HIV infection. The impact of Tb co-infection in the establishment and maintenance of the HIV reservoir is unclear.MethodWe enrolled 13 HIV-infected patients with microbiologically confirmed Tb and 10 matched mono-HIV infected controls. Total HIV DNA in peripheral blood mononuclear cells (PBMCs), plasma interleukin-7 (IL-7) concentrations and the activities of indoleamine 2,3-dioxygenase (IDO) were measured for all the participants prior to therapy and after antiretroviral therapy (ART).ResultsAfter a duration of 16 (12, 22) months’ ART, patients co-infected with Tb who were cured of Tb maintained higher levels of HIV DNA compared with mono-HIV infected patients [2.89 (2.65- 3.05) log10 copies/106 cells vs. 2.30 (2.11–2.84) log10 copies/106 cells, P = 0.008]. The levels of on-ART HIV DNA were positively correlated with the baseline viral load (r = 0.64, P = 0.02) in Tb co-infected group. However, neither plasma IL-7 concentration nor plasma IDO activity was correlated with the level of on-ART HIV DNA.ConclusionsTb co-infection was associated with the increased surrogate marker of the HIV reservoir, while its mechanism warrants further examination.

Plasma indoleamine 2,3-dioxygenase activity as a potential biomarker for early diagnosis of multidrug-resistant tuberculosis in tuberculosis patients.

Purpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients.Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed.Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p<0.05, separately) among all the TB patients studied.Conclusion: Our findings confirmed that plasma IDO activity might have an auxiliary diagnosis value for early discrimination of MDR-TB patients from DS-TB patients. Among the TB patients with cavitary lung lesions, higher plasma IDO activity can indicate a higher risk of MDR-TB.

The role of IDO, IL-10, and TGF-β in the HCV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.

Indoleamine-2,3-dioxygenase (IDO) is an enzyme that catalyzes tryptophan to kynurenine and studies have revealed that IDO play a vital role in regulation of liver immunity and inflammation activities. This study investigated the association between plasma IDO and disease severity and the possible marker role of IDO in the inflammatory process of hepatitis C. In this study, 80 individuals with HCV infection were retrospectively selected. Plasma levels of IDO, IL-10, and TGF-β were assayed by ELISA. Clinical characteristics of patients, including the levels of ALT, AST, and total bilirubin (TBil) were collected from clinical databases. HCV-related liver cirrhosis (HC-Cirr) and HCV-related Hepatocellular carcinoma (HCV-HCC) had significantly high plasma levels of IDO compared to other patient groups and healthy controls. Plasma IL-10 level were significantly greater in all chronic liver disease groups and with respect to TGF-β, the level was high in all the selected patients with HCV infection compare with controls. Moreover, HCV-HCC patients showed highest values for both IL-10 and TGF-β, with significant difference compared with other groups. In addition, plasma IDO was positively correlated with TGF-β among all patients with HCV infection (r = 0.4509, P < 0.0001), with IL-10 in CHC patients (r = 0.4787, P = 0.0047), with TBil in HCV-Cirr patients (r = 0.4671; P = 0.0093). High level of IDO and TGF-β is associated with hepatocyte necrosis and intrahepatic inflammation, and may be used as an index of disease progression for patients with chronic HCV infection.

Plasma Indoleamine 2, 3-Dioxygenase, a Biomarker for Tuberculosis in Human Immunodeficiency Virus-Infected Patients.

There is no biomarker for diagnosing active tuberculosis in patients with human immunodeficiency virus (HIV) infection. Indoleamine 2, 3-dioxygenase (IDO) is an immunoregulatory enzyme that breaks down tryptophan (Trp) to metabolites known as kynurenines (Kyns). We investigated whether IDO activity, as measured by the ratio of Kyn to Trp, could be used to diagnose or predict active tuberculosis disease in HIV-infected adults. Kyn and Trp concentrations were measured using ultraperformance liquid chromatography mass spectrometry in plasma samples from 32 HIV-infected patients in whom active tuberculosis developed and who were followed up prospectively. We compared to 70 HIV-infected control subjects from the same cohort in whom tuberculosis did not develop, matched by age, sex, and CD4 cell count, and 37 unmatched HIV-infected patients with a diagnosis of pneumonia. Clinical parameters, including body mass index, CD4 cell count, HIV load, and C-reactive protein levels were analyzed. At the time of tuberculosis diagnosis, IDO activity was significantly higher in patients with tuberculosis than in controls (P < .001). Six months before tuberculosis diagnosis, IDO activity was significantly higher in all patients who later developed tuberculosis (P < .001) than controls. After 6 months of tuberculosis treatment, IDO activity in patients with tuberculosis declined to levels similar to those in controls. IDO activity was 4-fold higher in patients with tuberculosis than in those with pneumonia, and could be used to distinguish them. With a receiver operating characteristic curve, IDO activity had a sensitivity of 97%, a specificity of 99%, and positive and negative predictive values of 89% and 100% for detecting active tuberculosis disease. Plasma IDO activity is suitable as a biomarker of active tuberculosis in HIV-positive patients.

Haem-Enzymes Predictive of Coronary Artery Disease Are Present in Thoracic and Abdominal Aortic Aneurysm

Purpose: A reliable plasma biomarker for aortic aneurysm has proven elusive. Elevated plasma levels of the oxidative or immune regulatory haem-enzymes myeloperoxidase (MPO) or indoleamine 2,3-dioxygenase (IDO) can predict disease prevalence and clinical risk in coronary artery disease patients. We therefore studied the relationship of MPO and IDO with thoracic or abdominal aortic aneurysm. Methodology: In patients undergoing elective surgical or endovascular repair of thoracic (n = 14) or abdominal (n = 18) aortic aneurysm, preoperative plasma was analysed for MPO protein levels by ELISA or IDO activity (indexed as a ratio of IDO's product kynurenine and substrate tryptophan) and compared with healthy controls (n = 15). Plasma levels of other inflammatory markers (CRP, neutrophil elastase) were also measured. Surgically resected aortic wall samples were analysed for MPO protein by immunohistochemistry. Results: Patients with abdominal aneurysms [72 yrs (67-76)] were significantly older than those with thoracic aneurysms [57 yrs (52-70)] and healthy controls [31 years (29-36)] and more likely to have atherosclerosis as the aetiology of aortic disease (88.9% vs. 28.6% in thoracic aneurysm). Plasma IDO activity and CRP levels, but not MPO or elastase, were significantly elevated in patients with aortic aneurysm vs. healthy controls. MPO protein, however, was expressed in the intima and media of all aortic aneurysm specimens but not non-diseased aorta. Conclusion: The haem-enzymes MPO and IDO may be involved in human aortic aneurysm and their roles warrant further study in experimental animal models of aneurysm. Measurement of plasma IDO activity and CRP, but not MPO, may represent potential useful biomarkers for aortic aneurysm.

Prognostic value of indoleamine 2,3-dioxygenase activity and expression in nasopharyngeal carcinoma

Indoleamine 2,3-dioxygenase (IDO) is an enzyme with an immunosuppressive effect whose function is diverted by tumor cells to counteract immune cell functions, inducing immune escape of tumor cells. The aim of this study was to investigate the clinical significance of IDO in nasopharyngeal carcinoma (NPC). Compared to controls, NPC patients’ plasma IDO activity was significantly higher, especially among patients with metastatic cancer (p=0.005). The immunohistochemical analysis revealed that high IDO expression was observed in 74% of NPC tissues and the epithelial IDO expression was inversely correlated to T-cell infiltration. Kaplan–Meier survival analysis showed that whatever the localization, intratumoral or stromal, patients with a high IDO expression and low T-cell infiltration have significantly lower survival rates. Moreover, in multivariate analysis, intratumoral and stromal IDO expression were found to be independent prognostic factors for disease-free survival (p=0.016; HR: 3.52) and overall survival (p=0.015; HR: 4.76) respectively. Our findings provide evidence that IDO is involved in tumor immune evasion of NPC, suggesting that it could be a relevant therapeutic target for NPC.

Circulating Mir-153 Participates in Occurrence of Acute Graft-Versus-Host Disease By Down-Regulating Indoleamine-2,3-Dioxygenase

Background Indoleamine-2,3-dioxygenase (IDO) is able to catalyze the first and rate-limiting step in the catabolism of tryptophan, which is the essential amino acid for T cell proliferation. Many previous studies have proved that IDO is able to play important roles in immunosuppression-associated with tumor immunity, autoimmunity and chronic infection. Since donor T cells will be activated, proliferate, differentiate and finally lead to tissue injury, growing research paid more attention to the immunoregulatory role of IDO in the process of aGVHD. Our previous work also demonstrated that plasma IDO level was correlated with the severity of aGVHD. Increased IDO expression would serve as a protective molecular during aGVHD. However, the exact regulatory mechanism of IDO is still unclear. MicroRNAs (miRNAs) are a class of small non-coding RNA that negatively regulate gene expression by translational repression or induction of mRNA degradation. Recently, circulating miRNAs have been reported to be the promising biomarkers for various kinds of diseases. We speculated that miRNA that might regulate those GVHD-related molecules/cytokines expression including IDO, and the circulating miRNA that directed at IDO would serve as new potential biomarker for aGVHD. This study is to find the potential regulatory miRNA of IDO and investigate the correlation between plasma miRNA expression and aGVHD.Methods The potential regulatory miRNA for IDO was identified through bioinformatics analysis using TargetScan and Miranda. The regulatory function of target miRNA on IDO protein and gene was confirmed by Western Blot analysis and luciferase assay. Human plasma samples from 70 patients who underwent allo-HSCT from Sep 2012 to Jun 2013 were prospectively collected at +7 day(d), +14d, +21d, +30d, +45d, +60d, +90d and the occurrence of aGVHD from Peking University Institute of Hematology. All patients provided informed consent. This study was approved by the institutional review board at the Peking University Institute of Hematology (Protocol number 2013-42). Real-time quantitative PCR (RQ-PCR) analysis was performed to examine the miRNA expression of plasma at different time points posttransplant. Receiver operating characteristic (ROC) analysis was employed to determine the optimal cut-off value for predict the occurrence of aGVHD.Results Through bioinformatics analysis, we found the predicted target sites in its 3’UTR binding miRNA-153. The intracellular IDO protein would be reduced when miRNA-153 was transfected into interferon-gamma-treated Hela cells. Surprisingly, the mRNA expression level of IDO was also affected in miRNA-153 transfected cells obviously (P<0.001). In addition, luciferase assay in 293T cells showed that miRNA-153 was able to bind directly to the promoter region of IDO gene and affect its transcription. Luciferase activity dropped around 44% when wild-type construct was co-transfected into 293T cells with miRNA-153 (P=0.009). However, when the potential binding sites were mutated, this phenomenon could not be observed. This indicates that the IDO 3’UTR is normally targeted by endogenous miR-153. Among the 70 patients who underwent allo-HSCT, 35 patients developed into aGVHD and 35 patients did not. A significant difference in miRNA-153 expression levels between the two groups was confirmed at +7d (P<0.001). Furthermore, we used ROC analysis to evaluate the diagnostic accuracy. Plasma levels of miRNA-153 at day 7 could predict an impending aGVHD with a sensitivity of 38.71% and a specificity of 100%, and the area under the curve (AUC) was 0.898 (95%CI: 0.821-0.974, P<0.0001).Conclusions Our study suggested that miRNA-153 might participate in occurrence of aGVHD by down regulating IDO and might be a putative target for novel aGVHD therapy. The plasma level of miRNA-153 at +7d after allo-HSCT would be a good biomarker for predicting the occurrence of aGVHD. DisclosuresNo relevant conflicts of interest to declare.

The role of plasma IDO activity as a diagnostic marker of patients with colorectal cancer

High levels of indoleamine 2,3-dioxygenase (IDO) are involved in tumour escape mechanisms. The aim of this study is the evaluation of L-kynurenine of plasma as marker of diagnostic and prognostic in patients with colorectal cancer. The study included 78 patients with colorectal cancer, of whom 15 % were in stage I/II, 30 % in stage III, and 55 % in stage IV, and was compared with a control group of 70 healthy subjects. The receiver operating characteristic (ROC) curve analysis showed an area under the curve of 0.917, with a specificity of 100 % and with a sensitivity to detect cancer of the colon of 85.2 %, taking 1.83 μM as a cut-off point. The overall survival analysis also indicated that patients with low levels of L-kynurenine in plasma increased survival rate after 45 months of follow-up (P = 0.032). These results show that the plasma levels of L-kynurenine could be a good biomarker to differentiate individuals with colorectal cancer from healthy individuals.

Increased Plasma Indoleamine 2,3-Dioxygenase Activity and Interferon-γ Levels Correlate with the Severity of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism that plays an important role in the induction of immune tolerance. To evaluate the expression levels of IDO and interferon (IFN)-γ in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify the correlation between IDO activity, IFN-γ, and acute graft-versus-host disease (aGVHD), we measured IDO mRNA expression in peripheral blood mononuclear cells in 89 allo-HSCT patients by reverse transcription-polymerase chain reaction. The IDO activity in plasma was also performed by reverse-phase high-performance liquid chromatography; plasma IFN-γ was detected by a standard enzyme-linked immunosorbent assay. IDO mRNA was detected in 55 of 74 patients (74.32%) with aGVHD. Of patients without aGVHD, only 2 of 26 expressed IDO mRNA (7.69%); none of 8 healthy volunteers was positive for IDO expression. Plasma IDO activity was much higher in aGVHD patients than in those without aGVHD (4.74 ± 3.35 vs 1.79 ± 1.02, respectively; P < .0001) or in healthy control subjects (4.74 ± 3.35 vs 1.77 ± .22; P < .0001). Patients with severe (grade III/IV) aGVHD had much higher IDO activity than those with mild (grade I/II) aGVHD (6.57 ± 3.34 vs 2.46 ± 1.41; P < .0001). Meanwhile, there was a significant increase in plasma IFN-γ level in aGVHD patients (P = .0043). IDO activity decreased after alleviation of aGVHD, whereas fluctuation of plasma IDO was also observed upon the recurrence of aGVHD. Plasma IDO activity was correlated with the level of plasma IFN-γ (r = .8288; P < .0001). Using receiver-operating characteristic curves analysis, the sensitivity and specificity for evaluation of aGVHD were determined. The area under the curve of IDO activity was higher than that of IFN-γ (.852 vs .694) with a sensitivity and specificity for IDO of 81% and 78%, respectively, whereas the sensitivity and specificity for IFN-γ were 41% and 93%, respectively. IDO mRNA was expressed in blood mononuclear cells of patients with aGVHD. Plasma IDO activity was elevated in aGVHD patients and was correlated with the severity of aGVHD. In combination with plasma IFN-γ, IDO activity may represent a potential biomarker for the diagnosis and evaluation of aGVHD after allo-HSCT. Intervention of the IDO pathway may also represent an alternative way to overcome steroid-resistant aGVHD.

Plasma Indoleamine 2,3-Dioxygenase and Arginase Type I May Contribute to Decreased Blood T-Cell Count in Hemodialysis Patients

Background: Acquired immunity is impaired in hemodialysis (HD) patients, and decreased T-cell number may contribute. Indoleamine 2,3-dioxygenase (IDO) and arginase type I (ARG) catabolize tryptophane and arginine, respectively, and exert proapoptotic and antiproliferative effects on T-cells. Plasma levels of IDO and ARG and their relation to blood T-cell number were evaluated in HD patients. Methods: Thirty-two HD patients and 20 healthy controls participated in the study. Plasma IDO and ARG were measured by means of enzyme-linked immunosorbent assay. T-cell number was assessed by means of flow cytometry. Results: IDO concentration was significantly higher in HD patients than in healthy volunteers (44.30 ± 31.83 ng/mL vs. 21.28 ± 26.21 ng/mL, p = 0.009). There was a trend for higher ARG concentration in HD patients (13.43 ± 11.91 ng/mL) than in healthy volunteers (9.56 ± 4.03 ng/mL), which, however, did not reach statistic significance (p = 0.099). Absolute T-cell count was significantly lower in HD patients than in healthy controls (1176.99 ± 567.71 cells/mm3 vs. 1519.85 ± 594.96 cells/mm3, p = 0.040). Absolute blood T-cell number was inversely related to plasma IDO (r = −0.490, p = 0.004) and to plasma ARG (r = −0.387, p = 0.029) concentrations. Conclusions: Plasma IDO and ARG may contribute to decreased blood T-cell count in HD patients.

Changes in the levels of thioredoxin and indoleamine-2,3-dioxygenase activity in plasma of patients with colorectal cancer treated with chemotherapy

Increased oxidative stress and indoleamine-2,3-dioxygenase (IDO) activity have been reported in cancer, but their relationship with chemotherapy remains unknown. The aim of the present study was to examine wether the chemotherapy treatments used in colorectal cancer had an additional effect on oxidative stress and on IDO activity. Plasma samples were collected from 27 colorectal cancer patients on cytostatic treatment, 27 with cytostatic drugs plus monoclonal antibodies (cytostatic-Mabs) and 15 non-treated patients. All patients with colorectal cancer had high plasma malondialdehyde (MDA), thioredoxin (Trx) levels, and elevated IDO activity in plasma (IDOp) and in dendritic cells (IDOc). This study shows that treatment with cytostatics have an effect on oxidative stress by increasing MDA levels and by decreasing Trx levels and IDO activity. However, treatment with cytostatic-Mabs showed no effect on MDA levels but decreased Trx levels, and the IDO activity showed values similar to the healthy group. Significant correlations between plasma IDO activity and the levels of Trx (r = 0.2062, p < 0.05) and MDA (r = 0.2873, p < 0.005) were observed. Furthermore, our study suggests that IDO activity measured as kynurenine levels could be used as a marker of the response to the chemotherapy treatments, although further studies are necessary.

Plasma Indoleamine 2,3-Dioxygenase Concentration is Increased in Hemodialysis Patients and May Contribute to the Pathogenesis of Coronary Heart Disease

Introduction: Coronary heart disease (CHD) is the leading cause of death in hemodialysis (HD) patients. Inflammation contributes to the pathogenesis of atherosclerosis in this population. Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunomodulatory properties, was evaluated in HD patients with or without CHD. Methods: Of the total of 66 HD patients, 22 of them with CHD were confirmed by coronary angiography and 24 healthy volunteers were enrolled in the study. Plasma IDO was assessed by means of enzyme-linked immunosorbent assay. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) were also measured. Results: Compared with healthy volunteers, plasma IDO concentration was markedly increased in HD patients (median 8.04 ng/mL vs. 48.9 ng/mL). Serum IL-6 and CRP were also significantly increased in HD patients. Compared with HD patients without CHD, plasma IDO concentration was significantly increased in HD patients with CHD (median 38.6 ng/mL vs. 74.5 ng/mL). Neither IL-6 nor CRP differed between the last two groups. IDO was negatively correlated with IL-6 and CRP. Conclusion: IDO concentration is increased in HD patients and is increased further in HD patients with CHD. It remains to be elucidated if increased IDO plays a direct role in the pathogenesis of atherosclerosis or if it affects atherosclerosis indirectly by curtailing chronic inflammation or both.

Potential immunosuppressive function of plasma indoleamine 2,3‐dioxygenase in patients with aGVHD after allo‐HSCT

Given the function of indoleamine 2,3-dioxygenase (IDO) in the induction of immune tolerance as a T-cell inhibitor, we investigated whether plasma IDO levels correlate with the biological activity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Plasma levels of IDO were monitored by ELISA in 147 samples from 65 patients who fulfilled the diagnostic histopathological and/or clinical criteria of aGVHD and 16 episodes of infection after allo-HSCT. Elevated plasma IDO levels were associated with occurrence of infection or mild aGVHD (grade I-II). Most patients with grade III-IV aGVHD had relatively low levels of IDO compared to those with mild aGVHD or infection. Responses of aGVHD to immunosuppressive therapy were associated with a decrease in IDO levels in the majority of patients with mild aGVHD, whereas secondary infection was characterized by persistent or increased IDO levels after treatment. Although plasma IDO levels may indicate the severity and outcome of aGVHD and point to appropriate therapies through its function in immune tolerance, it is not aGVHD specific and may not be a distinguishing biomarker of aGVHD.

Indoleamine 2,3-dioxygenase is increased in hemodialysis patients and affects immune response to hepatitis B vaccination

Background Acquired immunity is impaired in hemodialysis (HD) patients. Indoleamine 2,3-dioxygenase (IDO) is inducible by inflammation and through tryptophan depletion and generation of kynurenine pathway products suppresses adaptive immune response. In the present study plasma IDO levels were assessed in HD patients. Its effect on response to HBV vaccination program was evaluated. Patients and methods Sixty-six HD patients and twenty-four healthy volunteers enrolled into the study. All the HD patients were initially vaccinated with four double doses of recombinant HBV vaccine. All doses were repeated in patients who had not responded after complete first vaccination series. Only one boost dose was being administered in patients with initial adequate antibody levels against the HBV surface antigen (anti-HBs > 10 IU/L) who then presented with reduced anti-HBs levels. IDO, CRP, IL-6 and TNF-α were measured by means of ELISA. Results Compared to healthy volunteers, IDO levels were twice higher in HD patients. CRP, IL-6 and TNF-α were also much higher in HD patients. IDO levels were almost twice higher in HD patients with inadequate response to HBV vaccination, than in those with adequate immune response. CRP, IL-6 and TNF-α did not differ between the two patients’ groups. IDO was negatively correlated with all markers of inflammation in HD patients. Conclusion IDO is increased in HD patients. It is possible that after its initial upregulation due to chronic inflammation, IDO curtails its own provoking agent, i.e., inflammation. Increased IDO suppresses adaptive immunity in HD patients, as it is assessed by the response to HBV vaccination.