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There is a need for the development of additional prognostic melanoma (e.g., head and neck melanoma) biomarkers to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapy. Biomarkers play an important role in the diagnosis and prognostic classification of various types of cancer and may be indicators of biological or pathological processes or responses to exposure or intervention, providing a physician with the data helpful for future decision making with regard to patient management. The advent of novel treatments and modalities for treating various stages of the disease with a notable objective response-to-survival ratio gave us good reason, in this review, to emphasize non-histological serological biomarkers for the correction and improvement in the efficacy of treatment as well as the prognosis of survival in patients with head and neck melanoma.

Aim – to evaluate myeloid-derived suppressor cell (MDSC) subset counts and their suppressor potential in axial spondyloarthritis (axSpA) patients, as well as to analyze changes in the studied parameters in biological therapy (BT).Materials and methods. The study included 50 axSpA patients receiving 1st line therapy (non-steroidal anti-inflammatory drugs ±sulfasalazine/methotrexate) and 44 ageand sex-related healthy donors. Eight patients were initiated with BT (TNFαor IL-17 inhibitors). Peripheral blood granulocytic (G-MDSC), monocytic (M-MDSC) MDSCs, early-stage differentiation MDSCs (E-MDSC), and inhibitory molecule expression (PDL1, Arg-1, and IDO) were evaluated by flow cytometry.Results. The axSpA patients were characterized by increased G-MDSC counts (р

Objective: To investigate whether IL-6 using in early pregnancy can improve the pregnancy outcome of recurrent spontaneous abortion （RSA） mice and its relevant mechanism, providing new ideas for RSA clinical treatment. Methods: CBA/J×DBA/2 RSA model mice were constructed, and randomly divided the pregnant mice into five groups: control group, 0.1 ng/ml IL-6 group, 1 ng/ml IL-6 group, 10 ng/ml IL-6 group and 100 ng/ml IL-6 group. IL-6 was not injected in control group, while different concentrations of IL-6 were respectively injected into other groups on the 0.5 day of pregnancy. Pregnant rats were killed at 13.5 d and the embryo loss rate was calculated, the placental tissue was taked out, and expressions of IL-6 and indoleamine 2, 3-dioxygenase （IDO） in tissues were detected by Western blot. Results: Embryo absorption rates of 0.1 ng/ml IL-6 group, 1 ng/ml IL-6 group, 10 ng/ml IL-6 group and 100 ng/ml IL-6 group were obviously lower than that in control group （P=0.002 4, P=0.007 0, P=0.027 0, P=0.031 0）. IL-6 of exogenous injection was positive correlated with that expressed in mice placental tissue（r=0.791, P=0.000 052）. IL-6 concentration of exogenous injection was between 0~1 ng/ml, which was positively correlated with IDO expression in placental tissue（r=0.868, P<0.000 1）, IL-6 was positively correlated with IDO expressed in placental tissue （r=0.982, P<0.000 1）. IL-6 concentration of exogenous injection was between 1~100 ng/ml, which was inversely correlated with IDO expression（r=-0.725, P=0.002）, and IL-6 was inversely correlated with IDO expressed in placental tissue（r=-0.972, P<0.000 1）. Conclusion: A single intraperitoneal injection of specific concentration of exogenous IL-6 to RSA mice can reduce embryo absorption rate of mice and modify their pregnancy outcome, which possible mechanism is the exogenous IL-6 induces expressions of IL-6 and IDO for a long term. Whether the IDO expression in placental tissue increase or not can be regarded as a mark for whether the specific concentration IL-6 can protect the pregnancy or not. [ABSTRACT FROM AUTHOR]

"Objective To investigate the correlation between cerebral hemodynamics, serum indoleamine 2,3-dioxygenase (IDO) and post-stroke cognitive impairment (PSCI), and to explore the predictive value of IOD for PSCI. Methods A total of 50 patients with acute ischemic stroke who were diagnosed and the onset being not more than 7 days in the Department of Neurology of the 900th Hospital of PLA Joint logistics Support Force from July 2020 to June 2021 were selected as the case group. According to the presence or absence of PSCI, the patients were divided into PSCI group (n=30) and non-PSCI (PSNCI) group (n=20), and 50 healthy individuals during the same period were selected as the control group (n=50). ELISA was used to detect the serum IDO levels of the enrolled population. Transcranial color Doppler ultrasound (TCCD) breath-holding test was performed and relevant data was recorded, breath holding index (BHI) was calculated as an evaluation index of cerebral hemodynamics. ROC curve was used to analyze the predictive efficacy of IDO level on PSCI. Results There were statistically significant differences in serum levels of D-dimer and N-terminal pro-brain natriuretic peptide (NT-proBNP) among the three groups (P＜0.05). The serum IDO levels in the control group, PSNCI group, and PSCI group were (0.23±0.05), (0.25±0.02), and (0.31±0.03) ng/mL, respectively, with statistically significant differences among the three groups (F=41.092, P＜0.01). Compared with the PSNCI group, the PSCI group showed an increase in IDO levels (P＜0.05), while there was no statistically significant difference in D-dimer and NT-proBNP levels (P＞0.05). There was no significant difference in BHI among the three groups (P＞0.05). No significant difference was found in lesion location between the PSCI group and the PSNCI group (χ2=15.478, P=0.113). The predictive efficacy was highest when the IDO level cutoff value was 0.277 ng/mL, with a area under the ROC curve (AUC) of 0.938, sensitivity of 83.3%, and specificity of 95.0%. Conclusion There is a significant correlation between serum IDO levels and PSCI, but the relationship between hemodynamic indicators and the occurrence of PSCI is still unclear. Early detection of IDO levels after acute ischemic stroke is helpful for the early identification and diagnosis of PSCI."

Objective: The objective of this study was to observe the changes in the levels of indoleamine 2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) in patients with major depressive disorder (MDD) and investigate their potential role as novel biomarkers for diagnosing MDD. Methods: A total of 55 MDD patients and 55 healthy controls (HC) were enrolled in the study. The severity of MDD was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24) before and after treatment. The serum concentrations of IDO and TDO were measured at baseline and after treatment. The correlations between the serum levels of IDO and TDO and HAMD-24 scores were evaluated using Pearson's correlation test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the area under the curve (AUC) of serum levels of IDO and TDO for discriminating MDD patients from HC. Results: The serum IDO and TDO concentrations were significantly higher in patients with MDD at baseline than in healthy controls, and decreased significantly after 2 weeks or 1 month of treatment. The levels of IDO and TDO were significantly positively correlated with HAMD-24 scores. Furthermore, the AUC values for IDO and TDO were 0.999 and 0.966, respectively. Conclusion: The study suggests that serum IDO and TDO may serve as novel biomarkers for diagnosing MDD. These findings may lead to a better understanding of the pathogenesis of MDD and the development of new therapeutic targets. [ABSTRACT FROM AUTHOR]

There is a need for the development of additional prognostic melanoma (e.g., head and neck melanoma) biomarkers to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapy. Biomarkers play an important role in the diagnosis and prognostic classification of various types of cancer and may be indicators of biological or pathological processes or responses to exposure or intervention, providing a physician with the data helpful for future decision making with regard to patient management. The advent of novel treatments and modalities for treating various stages of the disease with a notable objective response-to-survival ratio gave us good reason, in this review, to emphasize non-histological serological biomarkers for the correction and improvement in the efficacy of treatment as well as the prognosis of survival in patients with head and neck melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of B-cells frequently encountered among people living with HIV. Immunological abnormalities are common in immunocompetent individuals with DLBCL, and are often associated with poorer outcomes. Currently, data on derangements of immunological proteins, such as cytokines and acute phase reactants, and their impact on outcomes in HIV-associated DLBCL (HIV-DLBCL) is lacking. This study assessed the levels and prognostic relevance of interleukin (IL)-6, IL-10 and Transforming Growth Factor Beta (TGFb), the acute phase proteins C-reactive protein (CRP) and ferritin; serum free light chains (SFLC) (elevation of which reflects a prolonged pro-inflammatory state); and the activity of the immunosuppressive enzyme Indoleamine 2,3-dioxygenase (IDO)in South African patients with DLBCL. Methods: Seventy-six patients with incident DLBCL were enrolled, and peripheral blood IL-6, IL-10, TGFb, SFLC and IDO-activity measured in selected patients. Additional clinical and laboratory findings (including ferritin and CRP) were recorded from the hospital records. Results: Sixty-one (80.3%) of the included patients were people living with HIV (median CD4-count = 148 cells/ul), and survival rates were poor (12-month survival rate 30.0%). The majority of the immunological proteins, except for TGFb and ferritin, were significantly higher among the people living with HIV. Elevation of IL-6, SFLC and IDO-activity were not associated with survival in HIV-DLBCL, while raised IL-10, CRP, ferritin and TGFb were. On multivariate analysis, immunological proteins associated with survival independently from the International Prognostic Index (IPI) included TGFb, ferritin and IL-10. Conclusion: Derangements of immunological proteins are common in HIVDLBCL, and have a differential association with survival compared to that reported elsewhere. Elevation of TGFb, IL-10 and ferritin were associated with survival independently from the IPI. In view of the poor survival rates in this cohort, investigation of the directed targeting of these cytokines would be of interest in our setting. [ABSTRACT FROM AUTHOR]

BackgroundIn the past decade, next-generation sequencing has spurred significant progress in the understanding of cytogenetic alterations that occur in meningiomas. Eighty percent of adult meningiomas harbor pathogenic somatic variants involving NF2, TRAF7, SMARCB1, KLF4, PI3K, or POLR2A. Somatic variants in TRAF7 associated with meningiomas usually localize to the gene's WD40 domains but are mutually exclusive to germline mutations, which cause a distinctive autosomal dominant syndrome.ObservationsThis case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis, and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus, and patent ductus arteriosus. Genetic testing of the meningioma specimen 7 years after biopsy showed a pathogenic p.R641C variant within the WD40 domain of the TRAF7 gene. Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent with postzygotic somatic mosaicism.LessonsThe authors report postzygotic somatic mosaicism for a p.R641C variant in the TRAF7 gene in a patient with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis and a constellation of systemic findings previously recognized in patients with germline mutations of this gene. This is the first report of optic nerve sheath meningioma in a patient with mutation in the TRAF7 gene.

ObjectiveTo determine the expression and functional roles of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) in leiomyoma.DesignExperimental study.SettingAcademic research laboratory.Patient(s)Women undergoing hysterectomy for leiomyoma.Intervention(s)Blockade of IDO1 and TDO2.Main outcome measure(s)Expression of IDO1 and TDO2 in leiomyoma and the effects of their inhibitors on the extracellular matrix.Result(s)Leiomyoma expressed significantly higher levels of IDO1 and TDO2 messenger ribonucleic acid (mRNA; 60.3%, 35/58 pairs and 98.3%, 57/58 pairs, respectively) and protein (54%, 27/50 pairs and 92%, 46/50 pairs, respectively) as well as the enzyme activity marker kynurenine (78.3%, 36/46 pairs for IDO1/TDO2) compared with levels in matched myometrium. The expression of TDO2 but not IDO1 mRNA was significantly higher in fibroids from African American compared with that in Caucasian and Hispanic patients. The TDO2 but not the IDO1 protein and mRNA levels were more abundant in fibroids bearing the MED12 mutation compared with results in wild-type leiomyomas. Treatment of leiomyoma smooth muscle cell and myometrial smooth muscle cell spheroids with the TDO2 inhibitor 680C91 but not the IDO1 inhibitor epacadostat significantly repressed cell proliferation and the expression of collagen type I (COL1A1) and type III (COL3A1) in a dose-dependent manner; these effects were more pronounced in leiomyoma smooth muscle cells compared with myometrial smooth muscle cell spheroids.Conclusion(s)These results underscore the physiological significance of the tryptophan degradation pathway in the pathogenesis of leiomyomas and the potential utility of anti-TDO2 drugs for treatment of leiomyomas.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme belonging to the kynurenine pathway. IDO activity has been suggested as a biomarker for diagnosis of chronic kidney disease. The aim of the study was to estimate the level of IDO, urea, creatinine, uric acid, phosphate, calcium, albumin, MDA, GSH, and activity of peroxidase, catalase, arylesterase in the serum of chronic renal failure (CRF) patients treated with dialysis compared to the healthy control group. The results showed a significant increment in IDO level in patients compared with the control. Linear regression analysis using the Pearson correlation coefficient showed that increased IDO level correlates positively with urea, creatinine, uric acid, phosphate, MDA level and peroxidase activity whereas negatively with albumin, calcium, glutathione level, catalase activity and glomerular filtration rate. We concluded that IDO level might be a possible marker of oxidative stress and inflammation in patients with CRF.

Kashif Asghar,1 Shaarif Bashir,2 Iftikhar Ali Rana,2 Muhammad Abu Bakar,3 Asim Farooq,1 Muhammad Hassan,1 Zukhruf Asif,1 Mahnoor Afzal,1 Iqra Masood,4 Muhammad Ishaq,2 Muhammad Tahseen,2 Sundus Bilal,5 Shafqat Mehmood,5 Nosheen Kanwal,6 Islah Ud Din,6 Asif Loya2 1Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan; 2Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan; 3Department of Cancer Registry and Clinical Data Management, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan; 4Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan; 5Department of Internal Medicine (Gastroenterology), Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan; 6Department of Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, PakistanCorrespondence: Kashif Asghar, Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, 7-A Block R-3, Johar Town, Lahore, Punjab, 54000, Pakistan, Tel +92-42-35905000, Fax +92-42-35945206, Email kashifasghar@skm.org.pkBackground/Aim: Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer that is modulated by the immune system. Programmed cell death ligand-1 (PD-L1) has emerged as a novel therapeutic target in various cancers. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is associated with poor prognoses in various cancer types. The aim of this study was to investigate the PD-L1 expression, and clinicopathological features of non-HCV and non-HBV-associated HCC patients, including IDO expression.Patients and Methods: In this study, immunohistochemical analysis was performed to analyze the expression of PD-L1 and IDO. Formalin-fixed paraffin-embedded HCC tumor tissues (n=50) were obtained from the pathology department, at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC) in Lahore, Pakistan between 2005 and 2022. All the patients were HBV and HCV negative. Furthermore, it was a rare group of patients with no previous history of any viral hepatitis. In addition, for categorical and continuous variables chi-square or Fisher exact test and Mann–Whitney U-test was performed.Results: Of 50 tissue specimens, PD-L1+ was observed in 21 [high: 12 (24%), low: 9 (18%)] and PD-L1- was observed in 29 HCC patients. IDO+ was observed in all 50 specimens [high: 42 (84%), low: 8 (16%)]. Additionally, both PD-L1 and IDO had high expression in 11 (22%) patients. While both PD-L1 and IDO had low expression in 2 (4%) patients. Furthermore, in IDO+/PD-L1- group, 20 (69%) out of 29 patients died while in the IDO+/PD-L1+ group, 9 (43%) out of 21 patients died.Conclusion: Evaluation of IDO and PD-L1 expression may add therapeutic advantage in non-HCV and non-HBV-associated HCC patients that overexpress IDO. Further validation in a larger cohort is warranted.Keywords: programmed cell death ligand-1, indoleamine 2, 3-dioxygenase, non-HCV HCC, non-HBV HCC, immune checkpoint molecules

Context: Implantation of fertilised eggs and survival of a semi-allogenic embryo rely on the interactions between the cells and molecules preparing the uterus. We investigated the effect of regulatory T cell (Treg) therapy on the mechanism of local immune tolerance of mice prone to spontaneous abortion. Methods: Naive T cells were stimulated in vitro with 17β-oestradiol (E2), progesterone (P4) and TGF-β1 for 96 h to generate induced Tregs (iTreg). The iTregs were injected into DBA/2-mated pregnant CBA/J female mice (abortion prone model). On day 14 of pregnancy, mice were killed and decidual and placental tissues were collected for cellular composition analysis. Results: Abortion prone mice (PBS treated) showed significantly lower survival rates (P < 0.0001), increased CD3+CD8+ (P < 0.05), lower IDO+ (P < 0.05) and increased natural killer cells (uNK) cell numbers (P < 0.001) in the uterus, as well increased NK cells in the placenta (P < 0.05) than in normal pregnant mice (CBA/J × BALB/c). Adoptive transfer of iTregs increased fetal survival in abortion-prone mice (P < 0.01) and histopathological evaluation revealed a significantly decreased number of uNK cells in the uterus of TGF-β1-, E2- and P4-iTregs (P < 0.05, P < 0.0001 and P < 0.05, respectively) than in the PBS treated group. In the placenta, we found significantly lower numbers of uNK cells from TGF-β1-, E2- and P4-iTregs than in the PBS treated group (P < 0.05, P < 0.05 and P < 0.01, respectively). Conclusions: We propose that modulation of uterine NK cell activity through immunotherapy using Treg cells should be given more attention as an immunological strategy in the treatment of recurrent miscarriage. Recurrent spontaneous abortion has been associated to imbalanced cellular immunological status. Adoptive transfer of induced regulatory T cells promoted survival rate and corrected dysregulated uterine natural killer cells. Induced regulatory T cells might have potential therapeutic benefits in women with recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Background: Indoleamine 2,3-dioxygenase (IDO), an enzyme in the first step of tryptophan catabolism, plays a role in the pathogenesis of various malignancies and inflammatory diseases. Although its pathogenesis is unclear, vascular dysregulation and chronic inflammation are the most common culprits for rosacea. Objectives: The aim of this study is to evaluate the relationship between IDO and rosacea and whether there is a correlation with disease severity. Methods: Fifty-two patients with rosacea and 29 healthy volunteers were recruited. The patients were grouped according to severity stage, period, and subtype of the disease. Serum IDO levels were measured with enzyme-linked immunosorbent assay. Results: Serum IDO levels were significantly higher in the patients with rosacea compared to the healthy controls (P < 0.001) and were significantly higher in the patients in remission period and with papulopustular type rosacea compared to the controls (P = 0.002 and P = 0.001, respectively). The serum IDO levels of the female rosacea patients were higher than those of the healthy female controls (P < 0.001). When the diagnostic value of the parameter was investigated, it was observed that the serum IDO level has high sensitivity (83.3%) and specificity (76.1%), with a cutoff value of 47.1 ng/mL for female rosacea patients. Conclusion: IDO was found to increase in rosacea patients. With the high specificity and sensitivity observed, especially in female patients, IDO may be a supporting parameter in the diagnosis of rosacea.

Abstract Background Clinical trial of IDO inhibitor or uses of micro-nutrient supplements during management of diseases is commonly done without having adequate basis for the practise. Tryptophan (Trp) is an essential amino acid needed for T-lymphocyte function, and indoleamine-2,3-dioxygenase (IDO) is a potent immunoregulatory molecule that catalyses the rate-limiting step of Trp degradation in the kynurenine (Kyn) pathway. Materials and methods Human IDO in the plasma samples was measured using ELISA in patients with non-infectious (asthma) and infectious diseases (pulmonary tuberculosis and COVID-19) compared with corresponding un-infected controls. Results Mean IDO activity in COVID-19 patients was significantly higher compared with corresponding control (p = 0.001) while mean IDO activity in pulmonary tuberculosis patients was non-significantly higher compared with corresponding control (p = 0.520), and mean IDO activity in asthma patients was non-significantly lower compared with corresponding control (p = 0.102). Conclusion Our data suggest that IDO activity as an innate immune factor is increased in infectious lung diseases (COVID-19 and pulmonary tuberculosis) but reduced in non-infectious disease (asthma) and that use of tryptophan supplementation or IDO inhibitor may not be necessary in all lung diseases.

Magdalena Massalska,1 Marzena Ciechomska,1 Ewa Kuca-Warnawin,1 Tomasz Burakowski,1 Anna Kornatka,1 Anna Radzikowska,1 Dariusz Pawlak,2 Barbara Muz,3 Adrianna Loniewska-Lwowska,4 Andrzej Palucha,5 Pawel Maldyk,6,7 Wlodzimierz Maslinski1 1Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland; 2Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 15-222, Poland; 3Department of Radiation Oncology, Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, 63108, USA; 4Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, 02-106, Poland; 5Genomed S.A. Ponczowa 12, Warsaw, 02-971, Poland; 6Department of Rheumoorthopaedic Surgery, National Institute of Geriatrics, Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland; 7Clinical Department of Orthopaedic and Traumatology of Locomotor System, Enfant-Jesus Clinical Hospital, Warsaw, 02-005, PolandCorrespondence: Magdalena Massalska, Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology, and Rehabilitation, Spartanska 1, Warsaw, 02-637, Poland, Tel/Fax +48 22 670 94 94, Email magdalena.massalska@spartanska.plBackground: Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic inflammation finally resulting in damaged joints. One of the RA development models suggests bone marrow (BM) as a place of inflammation development further leading to disease progression. We aimed to investigate the potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as indoleamine 2,3-dioxygenase (IDO) expression, CD4+Foxp3+ Treg induction, and T cell activation control. The expression of IDO-pathway genes was also examined in monocytes to estimate the tolerogenic potential in the periphery.Methods: Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory cytokines and CTLA-4-Fc. Next IDO expression, CD4+CD69+ and CD4+Foxp3+ percentage were estimated by PCR and FACS staining, respectively. Enzymatic activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated from RA patients and healthy controls.Results: We found that CTLA-4-Fc and IFN-γ stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan catabolism can inhibit mitogen-induced CD4+ T cells activation without influencing CD8+ cells, but did not control CD25 nor Foxp3 expression in BM cells. Significantly higher expression of selected IDO-pathway genes was detected on peripheral monocytes isolated from RA as compared to healthy controls.Conclusion: This study sheds light on some immunosuppression aspects present or induced in BM. The potential of IDO-mediated pathways were confirmed in the periphery, what may represent the promising candidates for therapeutic strategies in RA.Keywords: rheumatoid arthritis, bone marrow, CTLA-4-Fc, indoleamine 2,3- dioxygenase, CD4+Foxp3+, monocytes

Xuerun Peng,1,&ast; Zhipeng Zhao,1,&ast; Liwen Liu,2 Lan Bai,1 Rongsheng Tong,1 Hao Yang,3 Lei Zhong1 1Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China; 2Department of Obstetrics and Gynecology, Fengrun District People’s Hospital, Tangshan, Hebei, 063000, People’s Republic of China; 3POWERCHINA Chengdu Engineering Corporation Limited, Chengdu, Sichuan, 610072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Zhong, Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China, Email zhl7235301@163.com Hao Yang, POWERCHINA Chengdu Engineering Corporation Limited, Chengdu, 610072, Sichuan, People’s Republic of China, Email yanghao@chidi.com.cnAbstract: Indoleamine 2.3-dioxygenases (IDO1/2) and tryptophan 2.3-dioxygenase (TDO) are the initial and rate-limiting enzymes in tryptophan metabolism, which play an essential role in mediating immunosuppression in tumor microenvironment. Accumulating evidence has indicated that both IDO1 and TDO are highly expressed in many malignant tumors, and their expression is generally associated with reduced tumor-infiltrating immune cells, increased regulatory T-cell infiltration, as well as cancer progression and poor prognosis for malignancies. A large number of IDO1 and TDO inhibitors have been screened or synthesized in the last two decades. Thus far, at least 12 antagonists targeting IDO1 and TDO have advanced to clinical trials. In this account, we conducted a comprehensive review of the development of IDO1 and TDO inhibitors in cancer immunotherapy, particularly their clinical research progress, and presented the current challenges and corresponding solutions.Keywords: indoleamine 2, 3-dioxygenase, tryptophan-2, 3-dioxygenase, tryptophan metabolism, cancer immunotherapy, immune tolerance

Background: Indoleamine 2,3-dioxygenase (IDO), an enzyme in the first step of tryptophan catabolism, plays a role in the pathogenesis of various malignancies and inflammatory diseases. Although its pathogenesis is unclear, vascular dysregulation and chronic inflammation are the most common culprits for rosacea. Objectives: The aim of this study is to evaluate the relationship between IDO and rosacea and whether there is a correlation with disease severity. Methods: Fifty-two patients with rosacea and 29 healthy volunteers were recruited. The patients were grouped according to severity stage, period, and subtype of the disease. Serum IDO levels were measured with enzyme-linked immunosorbent assay. Results: Serum IDO levels were significantly higher in the patients with rosacea compared to the healthy controls (P < 0.001) and were significantly higher in the patients in remission period and with papulopustular type rosacea compared to the controls (P = 0.002 and P = 0.001, respectively). The serum IDO levels of the female rosacea patients were higher than those of the healthy female controls (P < 0.001). When the diagnostic value of the parameter was investigated, it was observed that the serum IDO level has high sensitivity (83.3%) and specificity (76.1%), with a cutoff value of 47.1 ng/mL for female rosacea patients. Conclusion: IDO was found to increase in rosacea patients. With the high specificity and sensitivity observed, especially in female patients, IDO may be a supporting parameter in the diagnosis of rosacea. [ABSTRACT FROM AUTHOR]

Preconditioning of mesenchymal stem/stromal cells (MSCs) with the inflammatory cytokine IFN-γ enhances not only their immunosuppressive activity but also their expression of HLA and proinflammatory genes. We hypothesized that prevention of the upregulation of inflammatory cytokines and HLA molecules in IFN-γ-primed MSCs would render these cells more immunosuppressive and less immunogenic. In this study, we discovered the following findings supporting this hypothesis: (1) activated human T cells induced the expression of IDO1 in MSCs via IFN-γ secretion and those MSCs in turn inhibited T-cell proliferation in an AHR-dependent fashion; (2) there was no difference in the expression of IDO1 and HLA-DR in MSCs after priming with a low dose (25 IU/mL) versus a high dose (100 IU/mL) of IFN-γ; (3) the transient addition of bortezomib, a proteasome inhibitor, to culture MSCs after IFN-γ priming decreased the expression of HLA-DR, inflammatory cytokine genes and Vcam1 while increasing the expression of IDO1 and the production of L-kynurenine; finally, MSCs primed with a combination of a low dose of IFN-γ and bortezomib were more effective in inhibiting Th17-mediated idiopathic pneumonia syndrome (IPS) and chronic colitis than unprimed MSCs. Our results suggest that bortezomib significantly eliminates the unfavorable effects of IFN-γ priming of MSCs (increased expression of MHC molecules and inflammatory cytokines and cell aggregation genes) and simultaneously increases their immunosuppressive activity by upregulating IDO1. Taken together, our newly established MSC priming method may contribute to MSC-based cell therapy for inflammatory diseases. Graphical Abstract [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies. Elevated regulatory T cell (Treg) infiltration has a potent immunosuppressive function in tumor biology, which contributes to low survival in PDAC. Nonetheless, the crosstalk between malignant cells and tumor-infiltrating Tregs in PDAC is not well understood. Here, clinical data demonstrates that the insulin-like growth factor binding protein 2 (IGFBP2) is associated with Treg accumulation in the microenvironment of PDAC in humans. Additionally, IGFBP2 increases Treg infiltration in the tumor microenvironment and promotes disease progression in mouse PDAC. Bioinformatic analysis and mechanistic assessment reveals IGFBP2 upregulated indoleamine 2, 3-dioxygenase (IDO) by activating signal transducer and activator of transcription 3 (STAT3) signaling in PDAC cells, thus inducing Treg differentiation and an immunosuppressive tumor microenvironment. These findings provide mechanistic insights into an important molecular pathway that promotes an immunosuppressive microenvironment, which suggests the IGFBP2 axis as a potential target for improved immune response in PDAC. [ABSTRACT FROM AUTHOR]

AIM: To explore the effect of indoleamine 2,3-dioxygenase (IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus (A. fumigatus) keratitis. METHODS: C57BL/6 mice models of A. fumigatus keratitis were established by inoculating hyphae of A. fumigatus evenly on the corneas. The clinical scores and inflammatory cytokines expression were measured respectively on the 1st, 3rd, 5th day after infection. The 1-MT (1 mg/mL) was administered by gavage to exert an inhibitory effect on IDO during infection. The mice were divided into control group, 1-MT group, A. fumigatus (A.F.) group, and 1-MT+A.F. groups. The corneas were monitored by slit lamp microscopy, and recorded disease scores in 3d after infection. Myeloperoxidase (MPO) assay was done to evaluate the neutrophils infiltration. Immunofluorescence staining was used to detect the recruitment of neutrophils in murine corneas. The mRNA of inflammatory cytokines was measured with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The corneal inflammation and the clinical score reached the peak on the 3rd day after the corneal infection. The mRNA of inflammatory cytokines of the A.F. group reached the highest on the 3rd day after the infection accordingly. Meanwhile, the results of slit light photography indicated that inhibitors of IDO made inflammation more serious contrasted with the A.F. group on the 3rd day. Besides, imunofluorescence staining and MPO indicated that 1-MT enhanced the recruitment, infiltration and chemotaxis of neutrophils obviously in contrast to the A.F. group. RT-PCR indicated that 1-MT increased the expression of CXCL-1, ICAM-1, IL-1β, and IL-8 significantly. CONCLUSION: IDO participates in the pathogenesis of A. fumigatus keratitis and plays an important role in inducing immune protection by inhibiting neutrophils-related inflammatory reaction and suppressing recruitment and chemotaxis of the neutrophils.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) results in high susceptibility to infection. Although granulocytic myeloid-derived suppressor cells (gMDSC) are elevated in patients with HBV-ACLF, their role in HBV-ACLF pathogenesis is unknown. To elucidate the mechanism of gMDSC expansion and susceptibility to infection in HBV-ACLF patients, we analyzed the proportion of gMDSC in the peripheral blood and organ tissues of patients with HBV-ACLF and an ACLF mouse model established by continuous injection (eight times) of Concanavalin by flow cytometry and immunohistochemistry. We found that the proportion of gMDSC increased significantly in the blood and liver of patients with HBV-ACLF. This increase was positively correlated with disease severity, prognosis, and infection. gMDSC percentages were higher in peripheral blood, liver, spleen, and bone marrow than control levels in the ACLF mouse model. Immunofluorescence revealed that the gMDSC count increased in the liver of patients with HBV-ACLF as well as in the liver and spleen of ACLF mice. We further exposed peripheral blood monocyte cells from healthy donors to plasma from HBV-ACLF patients, recombinant cytokines, or their inhibitor, and found that TNF-α led to gMDSC expansion and significant upregulation of indoleamine 2, 3-dioxygenase (IDO), while blocking TNF-α signaling decreased gMDSC. Moreover, we detected proliferation and cytokine secretion of T lymphocytes when purified gMDSC was co-cultured with Pan T cells or IDO inhibitor and found that TNF-α-induced gMDSC inhibited T cell proliferation and interferon-γ production through the IDO signaling pathway. Lastly, the ability of gMDSC to phagocytose bacteria was low in patients with HBV-ACLF. Our findings elucidate HBV-ACLF pathogenesis and provide potential therapeutic targets.

Background: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T).Methods: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status.Results: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only.Conclusions: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation. [ABSTRACT FROM AUTHOR]

Background: Tryptophan 2,3-dioxygenase (TDO2) is one of the emerging immune checkpoints. Meanwhile, TDO2 is also a key enzyme in the tryptophan (Trp)--kynurenine (Kyn) signaling pathway. Many studies have evaluated that TDO2 is highly expressed in various malignant tumor patients and plays a prognostic role. However, the sample size of a single prognostic study was small, and the results were still controversial. Methods: We used Stata software and referenced the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement to conduct a meta-analysis on TDO2 and its clinical features and prognosis. We searched the PubMed, Cochrane Library, and Web of Science databases to find publications concerning TDO2 expression in malignant tumor patients up to June 2021. We used the Newcastle--Ottawa Scale (NOS) to evaluate the bias risk of the included literature. Risk ratios (RRs) and hazard ratios (HRs) were used for clinical outcomes, specifically overall survival (OS) and progression- free survival (PFS). In addition, we used data from The Cancer Genome Atlas (TCGA) to verify our conclusions. Results: Nine studies including 667 patients with malignant tumors were identified. Our results suggested that overexpression of TDO2 was statistically correlated with poor OS and poor PFS (HR = 2.58, 95% CI = 1.52--4.40, p = 0.0005; HR = 2.38, 95% CI = 0.99--5.73, p = 0.05). In terms of clinicopathological characteristics, the overexpression level of TDO2 was statistically correlated with TNM (tumor--node--metastasis) stage (RR = 0.65, 95% CI = 0.48--0.89, p = 0.002) and regional lymph node metastasis (RR = 0.76, 95% CI = 0.59--0.99, p = 0.04). Subgroup analysis revealed the potential sources of heterogeneity. In addition, bioinformatics studies suggested that the level of TDO2 was high in malignant tumors and higher in cancer tissue than in matched paracarcinoma tissue. Gene enrichment analysis showed that TDO2 was closely related to immune response. Conclusion: Overall, TDO2 may be a biomarker for the survival and prognosis of patients with malignant tumors and a potential therapeutic target in the future. [ABSTRACT FROM AUTHOR]

The current studies associated with tumor biology continue to describe a high correlation between tryptophan (Trp) metabolism and tumor progression. These findings reflect the complex underlying mechanism of tumor development and highlight the need to explore additional drug targets for carcinoma‐associated diseases. In our study, we reported that elevated Trp metabolism was observed in highly malignant glioma tumor tissues from patients. The elevated Trp metabolism in glioma cells were induced by the overexpression of Trp 2,3‐dioxygenase 2 (TDO2), which further contributed to the production of the metabolite kynurenine (Kyn). Subsequently, the Kyn derived from Trp metabolism was able to mediate the activation of the aryl hydrocarbon receptor (AhR) and downstream PI3K/AKT signals, resulting in the strengthening of tumor stemness and growth. Meanwhile, the activation of the AhR could promote the process of epithelial−mesenchymal transition in gliomas through a TGF‐β‐dependent mechanism, leading to enhanced tumor invasion in vitro and in vivo. Inhibition of the AhR using StemRegenin 1 was demonstrated to suppress glioma growth and improve the outcome of traditional chemotherapy in subcutaneous tumor‐bearing mice, representing a promising therapeutic target for clinical glioma treatment. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a fatal brain tumor in adults with a bleak diagnosis. Expansion of immunosuppressive and malignant CD4 + FoxP3 + GITR + regulatory T cells is one of the hallmarks of GBM. Importantly, most of the patients with GBM expresses the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). While IDO1 is generally not expressed at appreciable levels in the adult central nervous system, it is rapidly stimulated and highly expressed in response to ongoing immune surveillance in cancer. Increased levels of immune surveillance in cancer are thus related to higher intratumoral IDO expression levels and, as a result, a worse OS in GBM patients. Conversion of the important amino acid tryptophan into downstream catabolite known as kynurenines is the major function of IDO. Decreasing tryptophan and increasing the concentration of immunomodulatory tryptophan metabolites has been shown to induce T-cell apoptosis, increase immunosuppressive programming, and death of tumor antigen-presenting dendritic cells. This observation supported the immunotherapeutic strategy, and the targeted molecular therapy that suppresses IDO1 activity. We review the current understanding of the role of IDO1 in tumor immunological escape in brain tumors, the immunomodulatory effects of its primary catabolites, preclinical research targeting this enzymatic pathway, and various issues that need to be overcome to increase the prospective immunotherapeutic relevance in the treatment of GBM malignancy. [ABSTRACT FROM AUTHOR]

Aim: Chronic inflammation is closely associated with tryptophan (TRP)-kynurenine (KYN) metabolic pathway. However, TRP-KYN pathway has not been fully elucidated in psoriasis, a systemic inflammatory disease with skin lesions and extracutaneous manifestations. Herein, we studied comprehensively serum profiles of TRP-KYN pathway metabolites in psoriatic patients (PSOs) to clarify the involvement of this pathway in the pathophysiology of psoriasis and to evaluate serum biomarkers reflecting systemic inflammation in PSOs. Methods: The concentrations of main TRP metabolites, TRP, KYN, 3-hydroxykynurenine (3HK), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), and anthranilic acid (AA), were determined by high-performance liquid chromatography in the sera from 65 PSOs and 35 healthy controls (HCs). The levels of these metabolites and the ratios of metabolites were compared between these subjects. The correlations between these values and the psoriasis area severity index (PASI) scores were analyzed. Skin samples from PSOs and HCs were subjected to immunohistochemical staining for kynureninase, catabolic enzyme from KYN or 3HK to downstream. Cytokine concentrations were comprehensively measured in the same samples and the correlations between the cytokine levels and TRP-KYN pathway metabolite levels were examined. Results: Serum TRP, KYN, and KYNA concentrations were lower and the 3HAA concentrations were higher in PSOs than in HCs. The ratios of 3HK/KYN, 3HAA/3HK, and 3HK/AA were higher in PSOs than in HCs. The AA levels and the ratio of AA/KYN were weakly positively correlated, and TRP, KYNA, and 3HK levels and the ratios of KYNA/KYN and 3HAA/AA were weakly negatively correlated with the PASI scores. The AA, KYN, and KYNA levels were positively correlated with the interferon gamma-induced protein 10 (IP-10) concentrations. Kynureninase expression was enhanced in the epidermis, both involved and uninvolved skin. Conclusions: Serum profiles of TRP-KYN pathway metabolites differed between PSOs and HCs. TRP-KYN pathway-associated processes, including kynureninase activation, may be involved in the pathogenesis of psoriasis, and thus serve as targets for psoriasis therapy.

Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) catalyse the same reaction, oxidative cleavage of L-tryptophan (L-Trp) to N -formyl-kynurenine. In both enzymes, the ferric form is inactive and ascorbate (Asc) is frequently used as a reductant in in vitro assays to activate the enzymes by reducing the heme iron. Recently, it has been reported that Asc activates IDO2 by acting as a reductant; however, it is also a competitive inhibitor of the enzyme. Here, the effect of Asc on human TDO (hTDO) is investigated. Similar to its interaction with IDO2, Asc acts as both a reductant and a competitive inhibitor of hTDO in the absence of catalase, and its inhibitory effect was enhanced by the addition of H2O2. Interestingly, however, no inhibitory effect of Asc was observed in the presence of catalase. TDO is known to be activated by H2O2 and a ferryl-oxo (FeIV=O) intermediate (Compound II) is generated during the activation process. The observation that Asc acts as a competitive inhibitor of hTDO only in the absence of catalase can be explained by assuming that the target of Asc is Compound II. Asc seems to compete with L-Trp in an unusual manner. [ABSTRACT FROM AUTHOR]

Background: Zingiber officinale (ginger) is used widely as a herb and medicine. It contains among its constituents 6-Gingerol (a phenol) and quercetin (a flavonoid) that possess anxiolytic and antidepressant properties, but the potential biochemical mechanism(s) of these effects has not been assessed, particularly in relation to serotonin synthesis and neurotransmission. Aims and Objectives: We investigated the anxiolytic-like activity of an aqueous ginger extract by evaluating its influence on behavior, and its effects on serotonin metabolism and on metabolism and disposition of the serotonin precursor tryptophan (Trp) in rats. Materials and Methods: An aqueous ginger extract was given orally in a single daily dose equivalent to 500 mg of ginger material per kg body weight for 3 weeks. The elevated plus maze test of anxiety and Trp metabolism and disposition and brain serotonin synthesis and turnover were assessed in Ginger-treated and control rats. Results: When compared with controls, ginger-treated rats showed a significant increase in the time spent in the open arm, indicative of decreased anxiety. However there was no effect on locomotor activity in open field test. The extract caused significant decreases in activities of liver Trp 2,3-dioxygenase and significant increases in concentrations of serum Trp and corticosterone and brain Trp, serotonin and the major serotonin metabolite 5-hydroxyindoleacetic acid. Conclusion: An aqueous ginger extract exerts an anxiolytic effect in a behavioral model of anxiety, which may be caused by increased serotonin synthesis, and influences tryptophan metabolism and disposition in a manner analogous to antidepressant drugs.

The immunomodulatory activity of mesenchymal stem/stromal cells (MSCs) to suppress innate and adaptive immune responses offers a potent cell therapy for modulating inflammation and promoting tissue regeneration. However, the inflammatory cytokine milieu plays a critical role in stimulating MSC immunomodulatory activity. In particular, interferon-γ (IFN-γ)-induced expression of indoleamine 2,3-dioxygenase (IDO) is primarily responsible for MSC suppression of T-cell proliferation and activation. Although pretreatment with IFN-γ is commonly used to prime MSCs for immunomodulatory activity prior to transplantation, the transient effects of pretreatment may limit the potential of MSCs to potently modulate immune responses. Therefore, the objective of this study was to investigate whether microparticle-mediated presentation of bioactive IFN-γ within three-dimensional spheroidal MSC aggregates could precisely regulate and induce sustained immunomodulatory activity. Delivery of IFN-γ via heparin-microparticles within MSC aggregates induced sustained IDO expression during 1 week of culture, whereas IDO expression by IFN-γ-pretreated MSC spheroids rapidly decreased during 2 days. Furthermore, sustained IDO expression induced by IFN-γ-loaded microparticles resulted in an increased and sustained suppression of T-cell activation and proliferation in MSC cocultures with CD3/CD28-activated peripheral blood mononuclear cells. The increased suppression of T cells by MSC spheroids containing IFN-γ-loaded microparticles was dependent on induction of IDO and supported by affecting monocyte secretion from pro- to anti-inflammatory cytokines. Altogether, microparticle delivery of IFN-γ within MSC spheroids provides a potent means of enhancing and sustaining immunomodulatory activity to control MSC immunomodulation after transplantation and thereby improve the efficacy of MSC-based therapies aimed at treating inflammatory and immune diseases. Stem Cells Translational Medicine 2017;6:223-237.

In this study, we synthesized a molecule GA-1MT (GM) composed of indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-d-tryptophan, 1MT) called NLG8189 and gallic acid (GA) and verified its therapeutic effect on B16F10 melanoma cells and an orthotopic tumor-bearing mouse model. The synthesized molecule GM was analyzed by 1H NMR and mass spectrometry (MS). In addition, we confirmed that GM could mediate the immune response in the B16F10 cell tumor model by flow cytometry and immunofluorescence. The synthesized GM molecule could increase the solubility of 1MT to enhance the drug efficacy and lower costs. Moreover, GM could inhibit melanoma growth by combining 1MT and GA. In vivo experiments showed that GM could effectively inhibit the expression of tyrosinase, regulate the proportion of CD4+ T cells, CD8+ T cells, and regulatory T cells (Treg cells) in tumors, and significantly suppress melanoma growth. The newly synthesized drug GM could more effectively inhibit melanoma than GA and 1MT alone or in combination.

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Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin+ LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1−CD83+ LCs; real immature IDO1−CD83− LCs; tolerogenic mature IDO1+CD83+ LCs; tolerogenic immature IDO1+CD83− LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR ≤ 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma. [ABSTRACT FROM AUTHOR]

The amino acid tryptophan (TRP) is critical for the expansion and survival of cells. During the past few years, the manipulation of tryptophan metabolism via indoleamine 2,3 dioxygenase (IDO) has been presented as a significant regulatory mechanism for tolerance stimulation and the regulation of immune responses. Currently, a considerable number of studies suggest that the role of IDO in T helper 2 (Th2) cell regulation may be different from that of T helper 1 (Th1) immune responses. IDO acts as an immunosuppressive tolerogenic enzyme to decrease allergic responses through the stimulation of the Kynurenine-IDO pathway, the subsequent reduction of TRP, and the promotion of Kynurenine products. Kynurenine products motivate T-cell apoptosis and anergy, the propagation of Treg and Th17 cells, and the aberration of the Th1/Th2 response. We suggest that the IDO-kynurenine pathway can function as a negative reaction round for Th1 cells; however, it may play a different role in upregulating principal Th2 immune responses. In this review, we intend to integrate novel results on this pathway in correlation with allergic diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes. Methods Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient’s serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later. Results We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients. Conclusions we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.

Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC.

: The immunomodulatory activity of mesenchymal stem/stromal cells (MSCs) to suppress innate and adaptive immune responses offers a potent cell therapy for modulating inflammation and promoting tissue regeneration. However, the inflammatory cytokine milieu plays a critical role in stimulating MSC immunomodulatory activity. In particular, interferon-γ (IFN-γ)-induced expression of indoleamine 2,3-dioxygenase (IDO) is primarily responsible for MSC suppression of T-cell proliferation and activation. Although pretreatment with IFN-γ is commonly used to prime MSCs for immunomodulatory activity prior to transplantation, the transient effects of pretreatment may limit the potential of MSCs to potently modulate immune responses. Therefore, the objective of this study was to investigate whether microparticle-mediated presentation of bioactive IFN-γ within three-dimensional spheroidal MSC aggregates could precisely regulate and induce sustained immunomodulatory activity. Delivery of IFN-γ via heparin-microparticles within MSC aggregates induced sustained IDO expression during 1 week of culture, whereas IDO expression by IFN-γ-pretreated MSC spheroids rapidly decreased during 2 days. Furthermore, sustained IDO expression induced by IFN-γ-loaded microparticles resulted in an increased and sustained suppression of T-cell activation and proliferation in MSC cocultures with CD3/CD28-activated peripheral blood mononuclear cells. The increased suppression of T cells by MSC spheroids containing IFN-γ-loaded microparticles was dependent on induction of IDO and supported by affecting monocyte secretion from pro- to anti-inflammatory cytokines. Altogether, microparticle delivery of IFN-γ within MSC spheroids provides a potent means of enhancing and sustaining immunomodulatory activity to control MSC immunomodulation after transplantation and thereby improve the efficacy of MSC-based therapies aimed at treating inflammatory and immune diseases.This study demonstrates that biomaterial-based presentation of cytokines within spheroidal mesenchymal stem/stromal cell (MSC) aggregates provides a means of locally concentrating and sustaining presentation of cytokines to potentiate MSC immunomodulatory activity. Overall, this approach could aid in overcoming the limitations of transient pretreatment strategies by continuously presenting cytokines within the MSC microenvironment and thereby maximizing the immunomodulatory potential of transplanted MSCs. Furthermore, this approach provides a means of inducing potent MSC immunomodulation, irrespective of unknown or ill-defined environmental inflammatory milieu, such as in chronic inflammation or when administered with immunosuppressants. Altogether, biomaterial-based engineering of the MSC microenvironment provides a means of controlling the function of transplanted cells to specifically direct their therapeutic activity and may improve MSC-based therapies aimed at treating a number of inflammatory and immune diseases.

Indoleamine 2,3-dioxygenase (IDO) plays important roles in maternal immune tolerance. Female Sprague Dawley rats (9-11 weeks old) were randomly divided into an autoplastic transplantation group (n = 75) and an allograft transplantation group (n = 300) was further divided into subgroups of ovarian transplantation, allograft ovarian transplantation, allograft ovarian transplantation with cyclosporine A treatment, allograft ovarian transplantation and transfection with IDO-expressing lentiviruses, and allograft ovarian transplantation and transfection with control lentiviruses. IDO was successfully transfected into the transplanted ovarian tissue. The survival rate, success rate of ovarian transplantation, period until estrous cycle restoration, and estrogen levels of rats that received IDO-expressing lentiviruses were significantly different from those of rats that underwent allograft transplantation and with control transfection (all P < 0.05), but not significantly different from those rats that received autoplastic transplantation (all P > 0.05). The number of ovarian follicles in the transplanted ovarian tissue of rats that received IDO-expressing lentiviruses was also significantly higher. The expression level of IDO protein detected by immunohistochemistry and western blotting was especially high in ovaries that had received IDO-containing lentiviruses. Naturally pregnant rats were found in each group postoperatively. These results indicated that IDO-expressing lentiviruses were successfully transfected into transplanted ovarian tissues of rats and that IDO was stably expressed within a certain time. These findings suggest that the expression level of IDO protein is associated with an enhanced success rate of ovarian tissue transplantation and a short restoration period of endocrine function., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The L-tryptophan (Trp) transport system is highly selective for Trp with affinity in the nanomolar range. This transport system is augmented in human interferon (IFN)-γ-treated and indoleamine 2,3-dioxygenase 1 (IDO1)-expressing cells. Up-regulated cellular uptake of Trp causes a reduction in extracellular Trp and initiates immune suppression. Recent studies demonstrate that both IDO1 and tryptophanyl-tRNA synthetase (TrpRS), whose expression levels are up-regulated by IFN-γ, play a pivotal role in high-affinity Trp uptake into human cells. Furthermore, overexpression of tryptophan 2,3-dioxygenase (TDO2) elicits a similar effect as IDO1 on TrpRS-mediated high-affinity Trp uptake. In this review, we summarize recent findings regarding this Trp uptake system and put forward a possible molecular mechanism based on Trp deficiency induced by IDO1 or TDO2 and tryptophanyl-AMP production by TrpRS., (© 2024 The Author(s).)

Indoleamine-2,3-dioxygenase (IDO) is the "rate-limiting" enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO's involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO's implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery. [ABSTRACT FROM AUTHOR]

Chorioamnionitis, an infection/inflammation of the fetomaternal membranes, is frequently associated with preterm delivery. The mechanisms of inflammation in chorioamnionitis are poorly understood. We hypothesized that neutrophils recruited to the decidua would be the major producers of proinflammatory cytokines. We injected intra-amniotic (IA) interleukin 1beta (IL-1beta) at ∼80% gestation in rhesus macaque monkeys, Macaca mulatta, delivered the fetuses surgically 24 h or 72 h after IA injections, and investigated the role of immune cells in the chorion-amnion decidua. IA IL-1beta induced a robust infiltration of neutrophils and significant increases of proinflammatory cytokines in the chorioamnion decidua at 24 h after exposure, with a subsequent decrease at 72 h. Neutrophils in the decidua were the major source of tumor necrosis factor alpha (TNFalpha) and IL-8. Interestingly, IA IL-1beta also induced a significant increase in anti-inflammatory indoleamine 2,3-dioxygenase (IDO) expression in the decidua neutrophils. The frequency of regulatory T cells (Tregs) and FOXP3 mRNA expression in the decidua did not change after IA IL-1beta injection. Collectively, our data demonstrate that in this model of sterile chorioamnionitis, the decidua neutrophils cause the inflammation in the gestational tissues but may also act as regulators to dampen the inflammation. These results help to understand the contribution of neutrophils to the pathogenesis of chorioamnionitis-induced preterm labor.

Indoleamine-2,3-dioxygenase (IDO) is the “rate-limiting” enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO’s involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO’s implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery.

Background: Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. More and more single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known about the impact of genetic variations of the IDO on the pathogenesis of PD. Methods: SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. Results: No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. Conclusions: The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

Host metabolism has recently gained more attention for its roles in physiological functions and pathologic conditions. Of these, metabolic tryptophan disorders generate a pattern of abnormal metabolites that are implicated in various diseases. Here, we briefly highlight the recent advances regarding abnormal tryptophan metabolism in HIV and Mycobacterium tuberculosis infection and discuss its potential impact on immune regulation, disease progression, and neurological disorders. Finally, we also discuss the potential for metabolic tryptophan interventions toward these infectious diseases.

Host metabolism has recently gained more attention for its roles in physiological functions and pathologic conditions. Of these, metabolic tryptophan disorders generate a pattern of abnormal metabolites that are implicated in various diseases. Here, we briefly highlight the recent advances regarding abnormal tryptophan metabolism in HIV and Mycobacterium tuberculosis infection and discuss its potential impact on immune regulation, disease progression, and neurological disorders. Finally, we also discuss the potential for metabolic tryptophan interventions toward these infectious diseases. [ABSTRACT FROM AUTHOR]

Background: Zingiber officinale (ginger) is used widely as a herb and medicine. It contains among its constituents 6-Gingerol (a phenol) and quercetin (a flavonoid) that possess anxiolytic and antidepressant properties, but the potential biochemical mechanism(s) of these effects has not been assessed, particularly in relation to serotonin synthesis and neurotransmission. Aims and Objectives: We investigated the anxiolytic-like activity of an aqueous ginger extract by evaluating its influence on behavior, and its effects on serotonin metabolism and on metabolism and disposition of the serotonin precursor tryptophan (Trp) in rats. Materials and Methods: An aqueous ginger extract was given orally in a single daily dose equivalent to 500 mg of ginger material per kg body weight for 3 weeks. The elevated plus maze test of anxiety and Trp metabolism and disposition and brain serotonin synthesis and turnover were assessed in Ginger-treated and control rats. Results: When compared with controls, ginger-treated rats showed a significant increase in the time spent in the open arm, indicative of decreased anxiety. However there was no effect on locomotor activity in open field test. The extract caused significant decreases in activities of liver Trp 2,3-dioxygenase and significant increases in concentrations of serum Trp and corticosterone and brain Trp, serotonin and the major serotonin metabolite 5-hydroxyindoleacetic acid. Conclusion: An aqueous ginger extract exerts an anxiolytic effect in a behavioral model of anxiety, which may be caused by increased serotonin synthesis, and influences tryptophan metabolism and disposition in a manner analogous to antidepressant drugs. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.