Indoleamine 2,3-dioxygenase Activity In Patients Research Articles

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.

Association of serum kynurenine/tryptophan ratio with poor glycemic control in patients with type2 diabetes.

The role of indoleamine 2,3-dioxygenase (IDO) has been shown in insulin resistance and metabolic syndrome. The present study aimed to measure serum IDO activity in patients with type 2 diabetes (T2DM) and to determine its association with glycemic control, oxidative stress, and insulin resistance. Seventy-four patients with T2DM and 74 healthy subjects were selected to participate in this study. Fasting serum biochemical parameters including fasting blood sugar (FBS), HbA1c, insulin, uric acid, albumin, tryptophan, kynurenine, and total antioxidant capacity (TAC) were measured. HOMA-IR, QUICKI, and HOMA-B were calculated using serum FBS and insulin values. IDO activity was estimated using kynurenine/tryptophan ratio (KTR). Data were analyzed using SPSS software (Version 15) and p < 0.05 was considered as a significant difference. The findings showed higher levels of FBS, HbA1c, HOMA-IR, and KTR in the patients compared to the controls. TAC and HOMA-B were significantly lowered in the T2DM patients compared to controls. KTR was significantly correlated with the level of HbA1c, and T2DM patients with poor glycemic control (HbA1c ≤ 8) had significantly higher level of KTR. HOMA-B was significantly correlated with serum tryptophan and inversely correlated with HbA1c. Serum KTR is increased in T2DM patients with poor glycemic control. Potential clinical implications and possible pathogenic roles of IDO in T2DM development should be further elucidated.

Indoleamine 2,3 dioxygenase (IDO) level as a marker for significant coronary artery disease

BackgroundIndoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in the kynurenine (Kyn) pathway of tryptophan (Trp) degradation, is modulated by inflammation, and is regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. Little is known about IDO activity in patients with active coronary artery disease (CAD).MethodsWe prospectively enrolled patients who were scheduled to undergo coronary angiography. Measurement of IDO, high-sensitivity troponin T (hs-TnT), and high-sensitivity C-reactive protein (hs-CRP) levels was performed at baseline, and IDO activity was monitored at the 6-month follow-up.ResultsThree hundred and five patients were enrolled. Ninety-eight patients (32.1%) presented with recent acute coronary syndrome (ACS). Significant difference in IDO, kynurenine, and hs-TnT between patients with and without significant CAD was observed. Baseline IDO activity, kynurenine level, and hs-TnT level were all significantly higher in significant CAD patients with 3-vessel, 2-vessel, and 1-vessel involvement than in those with insignificant CAD [(0.17, 0.13, and 0.16 vs. 0.03, respectively; p = 0.003), (5.89, 4.58, and 5.24 vs. 2.74 µM/g, respectively; p = 0.011), and (18.27, 12.22, and 12.86 vs. 10.89 mg/dL, respectively; p < 0.001)]. One-year mortality was 3.9%. When we compared between patients who survived and patients who died, we found a significantly lower prevalence of left main (LM) disease by coronary angiogram (6.1% vs. 33.3%, p = 0.007), and also a trend toward higher baseline kynurenine (5.07 vs. 0.79 µM/g, p = 0.082) and higher IDO (0.15 vs. 0.02, p = 0.081) in patients who survived.ConclusionImmunometabolic response mediated via IDO function was enhanced in patients with CAD, and correlated with the extent and severity of disease. Patients with LM disease had higher 1-year mortality. Lower level of IDO, as suggested by inadequate IDO response, demonstrated a trend toward predicting 1-year mortality.Trial registration TCTR Trial registration number TCTR20200626001. Date of registration 26 June 2020. “Retrospectively registered”.

Indoleamine 2,3 dioxygenase (IDO) as a new predictor for advance coronary artery diseases

Abstract Background Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in in the kynurenine (Kyn) pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. This response accelerates the resolution of inflamed tissues to protect them against collateral damage and facilitate tissue healing. A growing body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. Little is known about IDO activity in patients with active coronary artery disease (CAD). Purpose We hypothesized that IDO activity as reflected by Kyn/Trp ratio and Kyn levels correlated with coronary artery disease (CAD) severity and predicted 1-year major adverse cardiac events (MACE). Method We prospectively enrolled the patients whom underwent coronary angiography in our institute. We excluded the patients whom might have other non-cardiac causes of elevated inflammatory biomarkers such as rheumatoid arthritis, allergic asthma, and so on. Measurements of IDO, hs-troponin and hs-CRP levels were performed at baseline and IDO activity was monitored every 6 month at interval. Baseline demographic, coronary angiogram/interventions data were recorded. Significant CAD defined as &amp;gt;70% stenosis in major epicardial vessel. Patients were followed up for 1-year. MACE were pre-specified. Results Three-hundred and five patients were enrolled. Ninety-eight patients (32%) presented with acute coronary syndrome. There was a significant difference in IDO, kynurenine, and hs-troponin between patients with and without significant CAD (Table 1). In addition, baseline IDO activity, kynurenine and hs-troponin levels were significantly higher in significant CAD patients with 3-vessel, 2-vessel and 1-vessel involvements than those with insignificant CAD; (0.17 vs 0.14 vs 0.14 vs 0.04, p&amp;lt;0.01), (5.8 vs 4.5 vs 5.1 vs 2.9 μM/g, p&amp;lt;0.01) and (18.2 vs 12.4 vs 12.7 vs 11.1 mg/dL, p&amp;lt;0.001), respectively. Preliminary data in 287 patients with completion of 1-year follow up showed that 1-year mortality was 2.9%. In comparison between patients who survived and death, it demonstrated markedly higher baseline kynurenine (5.12 vs 0.54 μM/g, p&amp;lt;0.03) and IDO (0.15 vs 0.01, p&amp;lt;0.02) in the patients without 1-year mortality. Conclusion Immunometabolic response mediated through IDO function were enhanced in patients with CAD and correlated with the severity and extent of the disease. Patient with inadequate IDO response had a higher 1-year mortality. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Siriraj grant for research development and medical education of the Faculty of Medicine Siriraj Hospital

Serum Neopterin Levels and IDO Activity as Possible Markers for Presence and Progression of Hepatitis B

AbstractChronic Hepatitis B virus (HBV) is still one of the major reasons for liver related mortality and morbidity all around the world. This study aimed to investigate the possible relationship between the immune system activation and presence, as well as progression, of hepatitis B infection by monitoring the tryptophan degradation and serum neopterin levels in patients with HBV. 110 patients with HBV and 23 healthy subjects were included in the study. The patients had significantly higher neopterin levels and increased kynurenine to tryptophan ratios, which were most probably due to enhanced indoleamine 2,3-dioxygenase (IDO) activity compared to healthy control. A strong positive correlation was found between neopterin levels and IDO activity in patient group. Neopterin levels and IDO activity were markedly increased in patients with histological activity index (HAI) ≥4 compared to HAI&lt;4, and a significant correlation was found between neopterin and HAI. Moreover, there was a significant correlation between albumin levels and IDO activity in HBV patients. These findings suggest that tryptophan degradation results from IFN-γ-induced IDO activation, likewise depletion of albumin synthesis in HBV patients may result from diminished tryptophan availability. In conclusion, based on the study results, serum neopterin levels and IDO activity could provide additional immunological information for monitoring liver histological activity and can be used as prognostic markers in HBV disease.

Assessment of neopterin and indoleamine 2,3-dioxygenase activity in patients with seasonal influenza: A pilot study.

BackgroundSeasonal influenza is an important cause of morbidity and mortality worldwide. Immune activation after stimulation with interferon‐gamma leads to increased production of neopterin but also results in increased tryptophan catabolism through indoleamine 2,3‐dioxygenase (IDO). Our pilot study determined neopterin serum levels and IDO activity in patients with influenza infection and investigated whether neopterin is linked to clinical outcome parameters (mortality ≤30 days, acute cardiac events (ACE) length of hospitalization, ICU admission).MethodsNeopterin concentrations were analyzed in serum samples of 40 patients with a confirmed diagnosis of influenza infection and in‐hospital treatment for >24 hours. Data were compared to values of 100 healthy blood donors and 48 age‐matched pneumonia patients. In a subgroup of 14 patients, tryptophan and kynurenine concentrations, as well as kynurenine‐to‐tryptophan ratio, were analyzed.ResultsIn all influenza patients, neopterin concentrations were increased and significantly higher compared to those determined in patients with pneumonia and healthy controls. Positive correlations between the duration of hospitalization and neopterin were found. Significantly higher levels of kynurenine, kynurenine‐to‐tryptophan ratio, and lower levels of tryptophan were seen in influenza patients compared to healthy controls.ConclusionsNeopterin seems to be related to the course of the disease and could be a valuable biomarker to identify patients at an elevated risk of a worsened outcome; however, further prospective validation studies are needed to support the here presented preliminary results.

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.

Immune cells from patients with psoriasis are defective in inducing indoleamine 2,3-dioxygenase expression in response to inflammatory stimuli.

Indoleamine 2,3-dioxygenase (IDO) is an inducible enzyme that suppresses the immune response. The role of IDO as a negative regulator of inflammatory responses has been documented in several experimental autoimmune diseases. To explore the regulation of IDO by immune cells in psoriasis and its relation with disease severity. The expression and activity of IDO were assessed by reverse-transcriptase polymerase chain reaction, flow cytometry and high-performance liquid chromatography in peripheral blood of patients with moderate-to-severe plaque-type psoriasis. The ability of immune cells to express IDO in response to inflammatory stimuli was studied. The functional role of IDO expression was evaluated in a regulatory T cell (Treg) differentiation assay, using cocultures of immature monocyte-derived dendritic cells with autologous peripheral CD4+ T cells. Analysis of the kynurenine-to-tryptophan ratio in serum samples indicated higher IDO activity in patients with psoriasis than in healthy controls. However, correlation studies showed lower IDO activity in those patients with higher Psoriasis Area and Severity Index (PASI). Although myeloid dendritic cells from patients with psoriasis expressed higher levels of IDO than those from healthy controls, these cells did not upregulate IDO in response to a combination of tumour necrosis factor-α, interleukin (IL)-1β and IL-6 cytokines. The defective expression of IDO correlated with PASI. Immature monocyte-derived dendritic cells from patients with psoriasis also expressed low levels of IDO and induced CD4+ Treg differentiation poorly. Immune cells from patients with psoriasis have a defect in upregulating IDO in response to inflammation associated with the severity of psoriasis.

Serum indoleamine 2,3-dioxygenase and kynurenine aminotransferase enzyme activity in patients with ischemic stroke

We investigated the activation and pathophysiological roles of indoleamine 2,3-dioxygenase (IDO) and kynurenine aminotransferase (KAT) in patients with ischemic stroke. Patients were recruited from the acute stroke unit of a general hospital within 24hours post-stroke. The immune transmission turbidity method was used to determine the concentration of serum high-sensitivity C-reactive protein (hsCRP), apolipoprotein A-1 and apolipoprotein B. The concentrations of triglyceride, cholesterol, high density lipoprotein (HDL), low density lipoprotein and non-esterified fatty acids were determined using an enzymatic method. Tryptophan (TRP), kynurenine (KYN) and kynurenine acid (KYNA) concentrations were determined by high performance liquid chromatography. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological deficits at admission and 3weeks post-stroke. The IDO and KAT activity ratio were calculated by KYN/TRP and KYNA/KYN, respectively. The correlation between hsCRP and IDO, KAT and NIHSS score was also analyzed. A total of 81 patients with ischemic stroke and 35 normal controls were recruited. Lower TRP, KYNA, HDL and KAT activity ratio were found in the stroke group compared to the control group (p<0.05). The levels of hsCRP and IDO activity ratio were much higher in the stroke group than the control group (p<0.01). The IDO activity in patients with ischemic stroke showed a positive correlation with hsCRP (r=0.425, p=0.027). In addition, hsCRP and IDO levels were positively associated with the NIHSS score both at admission and 3weeks post-stroke. These data suggest an inflammatory response characterized by up-regulated IDO activation in ischemic stroke, which might be closely relevant to its pathophysiology.

Systemic tryptophan and kynurenine catabolite levels relate to severity of rhinovirus-induced asthma exacerbation: a prospective study with a parallel-group design

BackgroundPatients with allergic asthma have exacerbations which are frequently caused by rhinovirus infection. The antiviral tryptophan-catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is induced by interferon-γ and suppressed by Th2 mediators interleukin...

Indoleamine 2,3-dioxygenase activity as a potential biomarker of immune suppression during visceral leishmaniasis

Leishmania parasites induce an immunomodulation by subverting the host immune response towards a CD4(+) Th2 lymphocytic cell response that favors parasite persistence. Here, we report that after successful treatment of visceral leishmaniasis due to Leishmania infantum, an immune reconstitution syndrome revealing hip septic arthritis was associated with a switch from Th2 towards a Th1 cytokine profile, and a decrease in the level of immunomodulating factors, such as soluble HLA-G and indoleamine 2,3-dioxygenase (IDO) activity. We then measured IDO activity in a cohort of 39 patients and uninfected control subjects. Results showed significantly enhanced IDO activity in patients with visceral Leishmania infection, compared with uninfected control subjects (P < 0.001), but also compared with treated patients (P < 0.05). A decrease in IDO activity could constitute a relevant biomarker for the restoration of the immune response during visceral leishmaniasis.

P.2.d.006 How does amitriptyline treatment affect coenzyme Q levels and oxidative stress in patients diagnosed with depressive disorder?

We investigated the activation and pathophysiological roles of indoleamine 2,3-dioxygenase (IDO) and kynurenine aminotransferase (KAT) in patients with ischemic stroke. Patients were recruited from the acute stroke unit of a general hospital within 24 hours post-stroke. The immune transmission turbidity method was used to determine the concentration of serum high-sensitivity C-reactive protein (hsCRP), apolipoprotein A-1 and apolipoprotein B. The concentrations of triglyceride, cholesterol, high density lipoprotein (HDL), low density lipoprotein and non-esterified fatty acids were determined using an enzymatic method. Tryptophan (TRP), kynurenine (KYN) and kynurenine acid (KYNA) concentrations were determined by high performance liquid chromatography. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological deficits at admission and 3 weeks post-stroke. The IDO and KAT activity ratio were calculated by KYN/TRP and KYNA/KYN, respectively. The correlation between hsCRP and IDO, KAT and NIHSS score was also analyzed. A total of 81 patients with ischemic stroke and 35 normal controls were recruited. Lower TRP, KYNA, HDL and KAT activity ratio were found in the stroke group compared to the control group (p < 0.05). The levels of hsCRP and IDO activity ratio were much higher in the stroke group than the control group (p < 0.01). The IDO activity in patients with ischemic stroke showed a positive correlation with hsCRP (r = 0.425, p = 0.027). In addition, hsCRP and IDO levels were positively associated with the NIHSS score both at admission and 3 weeks post-stroke. These data suggest an inflammatory response characterized by up-regulated IDO activation in ischemic stroke, which might be closely relevant to its pathophysiology.

Indoleamine 2,3-Dioxygenase Activity and Expression in Patients With Chronic Lymphocytic Leukemia

Indoleamine 2,3-dioxygenase (IDO) activity and expression is increased in many hematological malignancies, but has not been previously studied in chronic lymphocytic leukemia (CLL). We determined IDO activity and expression in 49 patients with CLL. We found that IDO activity is increased in CLL. This may have some influence on CLL progression. Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in the catabolism of tryptophan, suppressing T-cell activity. IDO activity and expression are increased in many malignant diseases, including hematological malignancies. IDO expression can mediate immunotolerance to tumors. IDO activity and expression have not previously been studied in chronic lymphocytic leukemia (CLL). We measured IDO activity by calculating the kynurenine-tryptophan (kyn-trp) ratio. IDO and IDO2 gene expression was determined by using real-time polymerase chain reaction (PCR). In patients with CLL, the serum kyn-trp ratio--reflecting increased IDO activity--was significantly higher compared with controls, but in peripheral blood mononuclear cells (PBMCs)--mainly representing malignant B cells--the expression of genes encoding IDO and IDO2 enzymes was reduced. Increased IDO activity in patients with CLL may affect disease progression, although it originates from cells other than malignant B cells.

Effects of adalimumab therapy on disease activity and interferon-γ-mediated biochemical pathways in patients with rheumatoid arthritis

In patients with rheumatoid arthritis (RA), overwhelming inflammatory activity and immune activation are indicated by elevated concentrations of immune activation markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and neopterin. Furthermore, accelerated tryptophan (Trp) degradation by the enzyme indoleamine 2,3-dioxygenase (IDO) is detectable in blood samples of patients by an increased kynurenine (Kyn) to Trp ratio (Kyn/Trp). This study comprises 22 patients (20 women, 2 men) with long-standing, moderate to severe RA, who were treated with a monoclonal tumor necrosis factor (TNF)-antibody (Adalimumab 40 mg subcutaneously every other week) in addition to their concomitant, but inadequate anti-rheumatic therapies. Blood samples were collected before therapy and at week 12. ESR and CRP concentrations were measured within routine diagnostic. Serum concentrations of neopterin, Trp, and Kyn were determined by commercially available ELISA and by high performance liquid chromatography. Before therapy, disease activity as reflected by disease activity score 28 (DAS28) was significantly associated with concentrations of inflammation markers such as ESR (rs = 0.601, p < 0.01) and CRP (rs = 0.433, p < 0.05), but not with neopterin concentrations or Trp metabolic changes. Upon treatment, DAS28 improved significantly (median before therapy: 5.7 and after therapy: 3.1; p < 0.0001). During adalimumab treatment, only CRP decreased significantly (p < 0.05), while all other parameters investigated did not change significantly. Our results indicate that anti-TNF therapy does not influence neopterin concentrations or IDO activity in patients with RA, despite a highly significant improvement of patients' disease activity.

Kynurenine pathway in activated human macrophages

We investigated the activation and pathophysiological roles of indoleamine 2,3-dioxygenase (IDO) and kynurenine aminotransferase (KAT) in patients with ischemic stroke. Patients were recruited from the acute stroke unit of a general hospital within 24 hours post-stroke. The immune transmission turbidity method was used to determine the concentration of serum high-sensitivity C-reactive protein (hsCRP), apolipoprotein A-1 and apolipoprotein B. The concentrations of triglyceride, cholesterol, high density lipoprotein (HDL), low density lipoprotein and non-esterified fatty acids were determined using an enzymatic method. Tryptophan (TRP), kynurenine (KYN) and kynurenine acid (KYNA) concentrations were determined by high performance liquid chromatography. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological deficits at admission and 3 weeks post-stroke. The IDO and KAT activity ratio were calculated by KYN/TRP and KYNA/KYN, respectively. The correlation between hsCRP and IDO, KAT and NIHSS score was also analyzed. A total of 81 patients with ischemic stroke and 35 normal controls were recruited. Lower TRP, KYNA, HDL and KAT activity ratio were found in the stroke group compared to the control group (p < 0.05). The levels of hsCRP and IDO activity ratio were much higher in the stroke group than the control group (p < 0.01). The IDO activity in patients with ischemic stroke showed a positive correlation with hsCRP (r = 0.425, p = 0.027). In addition, hsCRP and IDO levels were positively associated with the NIHSS score both at admission and 3 weeks post-stroke. These data suggest an inflammatory response characterized by up-regulated IDO activation in ischemic stroke, which might be closely relevant to its pathophysiology.