Treg Lymphocytes Research Articles

Cholinergic Stimulation Improves Oxidative Stress and Inflammation in Experimental Myocardial Infarction

We previously reported that cholinergic stimulation with pyridostigmine (PY) induces anti-inflammatory cell recruitment soon after myocardial infarction (MI). In this study, we evaluated the anti-inflammatory effects of PY during the proliferative phase of cardiac repair by analyzing the infiltration of macrophages, Treg lymphocytes, oxidative stress and inflammatory cytokines. Wistar rats underwent control sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated (untreated infarcted group, I) or to receive PY (30 mg·kg(−1)·day(−1)) in the supplied water (infarcted treated group, I + PY). Blood pressure and heart rate variability were registered at day 5 post-MI. The animals were euthanized 7 days after thoracotomy, when the hearts were removed and processed for immunohistochemistry (CD68, CD206, FOXP3), cytokines (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, lipidic and protein peroxidation). PY treatment increased parasympathetic modulation, M2 macrophages and the anti-oxidant enzyme activity but reduced protein oxidation (carbonyls) and the concentration of IL-1β, IL-6, TNF-α and IL-10. Cholinergic stimulation induces parasympathetic neuro-immune modulation and anti-inflammatory cell enrollment as well as prevents oxidative stress and cytokine production after MI.

CAMP levels in lymphocytes and CD4+ regulatory T-cell functions are affected by dopamine receptor gene polymorphisms.

The neurotransmitter dopamine (DA) has prominent effects in the immune system and between the immune cells, CD4+ regulatory T (Treg) lymphocytes, a specialized T-cell subset crucial for the control of immune homeostasis, are especially sensitive to DA. Dopaminergic receptors (DR) are grouped into two families according to their pharmacological profile and main second messenger coupling: the D1 -like (D1 and D5 ), which activate adenylate cyclase, and the D2 -like (D2 , D3 and D4 ), which inhibit adenylate cyclase and exist in several variants that have been associated to clinical conditions such as schizophrenia, bipolar disorder, substance abuse and addiction. We aimed to examine, in venous blood samples from healthy volunteers, the relationship between the arbitrary DR score and DR functional responses in human lymphocytes. All the samples were genotyped for selected DR gene variants (DRD1: rs4532 and rs686; DRD2: rs1800497 and rs6277; DRD3: rs6280; DRD4: rs747302 and seven 48-base pair variable number tandem repeat (VNTR)) and a DR score was attributed to each participant. We have also tested whether DR gene polymorphisms might affect Treg cell ability to suppress effector T-cell function. To our knowledge, this is the first study showing a correlation between DR gene variants and human T lymphocyte function. The main results are that both D1 -like and D2 -like DR are functionally active in human lymphocytes, although the D1 -like DR stimulation results in stronger effects in comparison to the D2 -like DR stimulation. In addition, it seems that the DR genetic profile may affect the ability of lymphocytes to respond to dopaminergic agents. More investigations are needed about the possible clinical relevance of such findings.

Interleukin-10-regulated tumour tolerance in non-small cell lung cancer

Background:Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.Methods:Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.Results:Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.Conclusions:These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.

Hépatites auto-immunes : diagnostic immunologique

Autoimmune hepatopathies (AIHT) including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AIC), represent an impressive entities in clinical practice. Their pathogenesis is not perfectly elucidated. Several factors are involved in the initiation of hepatic autoimmune and inflammatory phenomena such as genetic predisposition, molecular mimicry and/or abnormalities of T-regulatory lymphocytes. AIHT have a wide spectrum of presentation, ranging from asymptomatic forms to severe acute liver failure. The diagnosis of AIHT is based on the presence of hyperglobulinemia, cytolysis, cholestasis, typical even specific circulating auto-antibodies, distinctive of AIH or PBC, and histological abnormalities as well as necrosis and inflammation. Anti-F actin, anti-LKM1, anti-LC1 antibodies permit to distinguish between AIH type 1 and AIH type 2. Anti-SLA/LP antibodies are rather associated to more severe hepatitis, and particularly useful for the diagnosis of seronegative AIH for other the antibodies. Due to the relevant diagnostic value of anti-M2, anti-Sp100, and anti-gp210 antibodies, the diagnosis of PBC is more affordable than that of PSC and AIC. Based on clinical data, the immunological diagnosis of AIHT takes advantage of the various specialized laboratory techniques including immunofluorescence, immunodot or blot, and the Elisa systems, provided of a closer collaboration between the biologist and the physician.

Role of PKA and PI3K in Leptin and Ghrelin Regulation of Adaptive Subpopulations of Regulatory CD4+ T-Lymphocyte Formation.

The role of phosphatidylinositol-3 kinase (PI3K) and protein kinase A (PKA) in leptin and ghrelin regulation of formation of adaptive (a) subpopulations of CD4+ T-lymphocytes(helper (h) cells producing interleukin-17A) (aTһ17) and of T-regulatory lymphocytes (aTreg) in the context of physiological pregnancy is established. It is shown that leptin at a concentration typical for the second half of pregnancy (trimesters II-III) enhances the differentiation of aTһ17 with a high level of interleukin-17A (IL-17A) production and the expression of the chemokine receptor CCR6 with the participation of PI3K. Simultaneously, leptin reduces formation of aTreg expressing the suppressor molecule CTLA-4, which determines the function of these cells. Ghrelin at a concentration characteristic of the first half of pregnancy (trimesters I-II), in contrast, enhances aTreg formation and, in parallel, reduces the level aTһ17 (that express CCR6) and the IL-17A production by aTh17. PKA, likewise PI3K, participates in regulatory effects of ghrelin on the formation of aTһ17 and aTreg. The combined action of leptin and ghrelin (via PKA participation) enhances formation of only aTreg, which determines the priority of this molecular mechanism and explains why the investigated hormones with reciprocal differentiating potential do not come into antagonism at the level of immune system cells during pregnancy.

Local Immunotherapy of Cancer: Innovative Approaches to Harnessing Tumor-Specific Immune Responses.

Modern cancer immunotherapies represent a major shift in paradigm with respect to how we understand innate and adaptive responses to malignancy. Successful tumors co-opt normal immunosurveillance mechanisms by potent interactions between the tumor and local draining lymph nodes. Tumor cells mediate a complex and dynamic immunoediting procedure that results in increased vascular efflux into the draining lymphatics, an immunosuppressive microenvironment rich in regulatory T-lymphocytes, dysfunctional antigen presentation, and downregulation of normal effector lymphocyte responses. Our current approach to reversing this process for antitumor effect involves mainly systemic administration of immunotherapeutic agents, many of which have become standard of care in the management of a variety of cancers. Despite this, we are still learning how best to administer these drugs alone and in combination to maximize efficacy while minimizing adverse events. Increasing evidence suggests that comparable efficacy may be achieved by local administration of immunotherapies in the tumor or tumor-draining lymph nodes with substantially lower doses and better tolerability, even with combination therapy. Herein, we review the literature on intratumoral and intranodal immunotherapies in preclinical models and early-phase studies, with particular emphasis on approaches potentially suitable for translation to larger-scale clinical trials.

Effects of early enteral nutrition on T helper lymphocytes of surgical septic patients

The aim of this study was to investigate the effects of early enteral nutrition (EEN) on T helper lymphocytes and the subpopulations ratios of surgical septic patients.We performed a retrospective study including 107 eligible patients from February 2014 to December 2015. Patients were divided into EEN, delayed enteral nutrition (DEN), or total parenteral nutrition (TPN) group according to the duration before enteral feeding. Th1, Th2, Th17, and Treg lymphocyte percentages were collected on days 3, 7, and 14 after admission. The disease severity and clinical outcome variables were also recorded.The Th1, Th17 percentages, and Th1/Th2, Th17/Treg ratios of EEN group were significantly lower than those of DEN or TPN group on the 14th day after admission (P < .05). Compared with TPN, DEN might have a tendency to decrease the Th1 and Th17 percentages. EEN could improve the disease severity and clinical outcomes of septic patients, however, no difference on 28-day mortality was found between EEN and DEN group.EEN could improve the dysregulation of Th1/Th2 and Th17/Treg ratios during early stage of sepsis. Compared with DEN, EEN could improve the disease severity and clinical outcomes, but not decrease the 28-day mortality of surgical septic patients.

Specific immunotherapy in allergic rhinitis

Allergic rhinitis is a common condition, with significant impact on quality of life depending on severity and quality of control. Allergen-specific immunotherapy (allergen-SIT) is the only known treatment able to alter the natural course of allergic rhinitis. Although well known to allergologists, it has yet to be fully adopted by the ENT community. This review, based on the most recent meta-analyses and clinical studies, shows that SIT significantly reduces symptoms and medication requirements (nasal corticosteroids, H1-antihistamines) in allergic rhinitis. It can reduce the risk of progression to asthma and, if initiated early enough, of developing new sensitizations. Immunobiological analysis shows an altered inflammatory profile following SIT, with immune tolerance involving T-regulatory lymphocyte induction and IgG production. Sublingual SIT with drops is as effective as subcutaneous SIT and is simpler to use, with less anaphylactic risk. Standardization of trial protocols in terms of treatment response assessment and side effect grading is recommended to improve comparative studies. Sublingual SIT with tablets has recently been introduced, providing a good opportunity for ENT practitioners to adopt the SIT approach in rhinitis triggered by allergy to pollens and, in the near future, to house dust mites.

Imbalances in T Cell-Related Transcription Factors Among Patients with Hashimoto’s Thyroiditis

Imbalances in effector T cell functioning have been associated with a number of autoimmune diseases, including Hashimoto's thyroiditis (HT). Differentiation of effector T helper (Th) 1, Th2, Th17 and regulatory T cell (Treg) lymphocytes is regulated by transcription factors, including Th1-specific T box (T-bet), GATA binding protein-3 (GATA3), retinoid-related orphan receptor (ROR)-α and forkhead box P3 (FOXP3). This study aimed to investigate Th1/Th2, Th1/Treg, Th2/Treg and Th17/Treg balances at the level of these transcription factors. This study took place between October 2015 and August 2016. Peripheral blood mononuclear cells were collected from a control group of 40 healthy women recruited from the Zahedan University of Medical Sciences, Zahedan, Iran, and a patient group of 40 women with HT referred to the Hazrat Ali Asghar Hospital, Zahedan. Total ribonucleic acid extraction was performed and the gene expression of transcription factors was quantitated using a real-time polymerase chain reaction technique. Expression of T-bet and GATA3 was significantly elevated, while FOXP3 expression was significantly diminished among HT patients in comparison with the controls (P = 0.03, 0.01 and 0.05, respectively). Expression of RORα was higher among HT patients, although this difference was not significant (P = 0.15). Expression of T-bet/FOXP3, GATA3/FOXP3 and RORα/FOXP3 ratios were increased among HT patients in comparison with the controls (P <0.02, <0.01 and <0.01, respectively). These results indicate that HT patients have imbalances in Th1/Treg, Th2/Treg and Th17/Treg lymphocytes at the level of the transcription factors, deviating towards Th1, Th2 and Th17 cells. Correction of these imbalances may therefore be therapeutic.

Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

AbstractTherapy for steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains suboptimal. Preclinical data demonstrate increased CD30 expression on activated CD8+ T cells during aGVHD. Brentuximab vedotin (BV) is an antibody-drug conjugate targeting CD30. We conducted a multicenter phase 1 trial in 34 patients to establish the maximum tolerated dose (MTD) of BV for SR-aGVHD treatment. A 3+3 cohort design was conducted initially with BV given weekly × 3 doses followed by maintenance dosing (initial dose 0.6 mg/kg IV weekly). Six patients were treated with the initial weekly dosing scheme; 2 of these patients died of neutropenic sepsis complications. The trial was subsequently revised to escalating cohorts of 5 patients treated every 2 weeks × 4 doses with a 4-week dose-limiting toxicity (DLT) period. Twenty-eight patients were treated with every-2-week dosing (n = 10 at 0.6 mg/kg; n = 18 at 0.8 mg/kg). MTD was defined at 0.8 mg/kg with 1 DLT observed (sepsis). At day 28, the overall response rate was 38.2% with 5 complete responses (CRs; 14.7%) and 8 very-good-partial responses (23.5%). An additional 7 patients achieved CR by day 56. With 12 months' follow-up on all patients, overall survival was 41% (95% confidence interval [CI], 25%-57%) at 6 months and 38% (95% CI, 22%-54%) at 12 months. CD30 expression on central memory CD8+, central memory CD4+, and regulatory T-lymphocyte subsets at enrollment was not associated with clinical response. BV is tolerable and has activity in SR-aGVHD and merits further investigation. This trial was registered at www.clinicaltrials.gov as #NCT01940796.

The regulation of immune cells by Lactobacilli: a potential therapeutic target for anti-atherosclerosis therapy.

Atherosclerosis is an inflammatory disease regulated by several immune cells including lymphocytes, macrophages and dendritic cells. Gut probiotic bacteria like Lactobacilli have been shown immunomodificatory effects in the progression of atherogenesis. Some Lactobacillus stains can upregulate the activity of regulatory T-lymphocytes, suppress T-lymphocyte helper (Th) cells Th1, Th17, alter the Th1/Th2 ratio, influence the subsets ratio of M1/M2 macrophages, inhibit foam cell formation by suppressing macrophage phagocytosis of oxidized low-density lipoprotein, block the activation of the immune system with dendritic cells, which are expected to suppress the atherosclerosis-related inflammation. However, various strains can have various effects on inflammation. Some other Lactobacillus strains were found have potential pro-atherogenic effect through promote Th1 cell activity, increase pro-inflammatory cytokines levels as well as decrease anti-inflammatory cytokines levels. Thus, identifying the appropriate strains is essential to the therapeutic potential of Lactobacilli as an anti-atherosclerotic therapy.

Bioactive growth hormone in older men and women: It's relationship to immune markers and healthspan

ObjectiveThe consequences of age-related decline in the somatotropic axis of humans are complex and remain largely unresolved. We tested the hypothesis that hGH measurements of plasma by bioassay vs immunoassay from samples obtained from free-living, elderly individuals would reveal a dichotomy in GH activities that are correlated with the functional status of the donors, i.e. their healthspan. DesignForty-one men and women of advanced age (men: N=16, age, 80.5±6.5years; height, 173.1±6.9cm; body mass, 81.8±13.0kg) and (women: N=25, age, 80.7±7.2years; height, 157.7±6.0cm; body mass, 68.8±17kg), were recruited for a cross-sectional study. Participants filled out PROMIS (Patient-Reported Outcomes Measurement Information System, U. S. Department of Health and Human Services) scales, undertook physical performance tests and had fasted blood samples obtained at rest for measurement of hormonal and immunology biomarkers. ResultsWhen measured by the well-established rat tibial line GH bioassay, one half of the plasma samples (n=20) contained bioassayable GH (bGH), but the other half (n=21) failed to mount increases in tibial plate width above saline injected controls. This difference did not correlate with the age, sex or physical functionality of the plasma donor. It also did not correlate with hGH concentrations measured by immunoassay. In those cases in which bGH was detected, various hierarchical regression models predicted that GHRH, c-peptide, VEGF, NPY, IL-4 and T-regulatory lymphocytes were associated with the difference and predicted bGH. ConclusionResults from this study suggest that the actions of bGH at the cellular level may be modified by other factors and that this may explain the lack of correlations observed in this study.

The Immune System As a New Possible Cell Target for AFP 464 in a Spontaneous Mammary Cancer Mouse Model.

Aminoflavone (AFP 464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP 464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor size, and growth rate in the estrogen dependent, Tamoxifen-sensitive spontaneous M05 mouse model. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, we investigated whether AFP 464 modulates the immune response in our mouse model. Studies on the effect of AFP 464 on the immune system were carried in BALB/c mice bearing M05 semi-differentiated mammary adenocarcinomas that express estrogen and progesterone receptors. Splenic cells and tumor inflammatory infiltrates were studied by cytometric analyses. The modulation of splenocytes cytotoxic activity by AFP 464 was also evaluated. We further investigated the effects of AFP 464 on peritoneal macrophages by evaluating metalloproteinase, arginase, and iNOS activities. We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes, and MDSCs, and induced a M1 phenotype in peritoneal macrophages of M05 tumor bearing mice. Therefore, we conclude that AFP 464 modulates immune response which collaborates with its anti-tumor activity. Our results place the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens. J. Cell. Biochem. 118: 2841-2849, 2017. © 2017 Wiley Periodicals, Inc.

Th17 and Treg lymphocytes as cellular biomarkers of disease activity in Granulomatosis with Polyangiitis.

Granulomatosis with Polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is a vasculitis of unknown etiology affecting predominantly small- to medium-sized vessels, usually involving the upper and lower respiratory tract and kidneys. Anti-neutrophil cytoplasmic autoantibodies are probably the initial cause of the inflammatory process that leads to the typical necrotizing lesions. In this issue of the European Journal of Immunology, Szczeklik etal. [Eur. J. Immunol. 2017. 47: 724-733] report some interesting findings on the possible involvement of T-cell subsets in the pathogenesis of the disease. This prospective study, performed on a large cohort of patients, identifies Th17 lymphocytes as the possible pathogenic subset of GPA, and Treg cells as the possible suppressors of the inflammatory process. These two subsets in peripheral blood could be used as cellular biomarkers of disease activity, and this would result particularly useful in the follow-up of patients once the immunosuppressive treatment has been initiated.

CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder

CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder

Treatment of Pediatric Acute Graft-versus-Host Disease—Lessons from Primary Immunodeficiency?

Allogeneic hematopoietic stem cell transplant (HSCT) is used to treat increasing numbers of malignant and non-malignant disorders. Despite significant advances in improved human leukocyte antigens-typing techniques, less toxic conditioning regimens and better supportive care, resulting in improved clinical outcomes, acute graft-versus-host disease (aGvHD) continues to be a major obstacle and, although it principally involves the skin, gastrointestinal tract, and liver, the thymus is also a primary target. An important aim following HSCT is to achieve complete and durable immunoreconstitution with a diverse T-cell receptor (TCR) repertoire to recognize a broad range of pathogens providing adequate long-term adaptive T-lymphocyte immunity, essential to reduce the risk of infection, disease relapse, and secondary malignancies. Reconstitution of adaptive T-lymphocyte immunity is a lengthy and complex process which requires a functioning and structurally intact thymus responsible for the production of new naïve T-lymphocytes with a broad TCR repertoire. Damage to the thymic microenvironment, secondary to aGvHD and the effect of corticosteroid treatment, disturbs normal signaling required for thymocyte development, resulting in impaired T-lymphopoiesis and reduced thymic export. Primary immunodeficiencies, in which failure of central or peripheral tolerance is a major feature, because of intrinsic defects in hematopoietic stem cells leading to abnormal T-lymphocyte development, or defects in thymic stroma, can give insights into critical processes important for recovery from aGvHD. Extracorporeal photopheresis is a potential alternative therapy for aGvHD, which acts in an immunomodulatory fashion, through the generation of regulatory T-lymphocytes (Tregs), alteration of cytokine patterns and modulation of dendritic cells. Promoting normal central and peripheral immune tolerance, with selective downregulation of immune stimulation, could reduce aGvHD, and enable a reduction in other immunosuppression, facilitating thymic recovery, restoration of normal T-lymphocyte ontogeny, and complete immunoreconstitution with improved clinical outcome as the ability to fight infections improves and risk of secondary malignancy or relapse diminishes.

Skewing toward Treg and Th2 responses is a characteristic feature of sustained remission in ANCA-positive granulomatosis with polyangiitis.

The objective of our study was to evaluate the T-helper (Th) and regulatory T (Treg) cell profile in ANCA-positive granulomatosis with polyangiitis (GPA) and its relation to disease activity. In a prospective study, we studied two groups of GPA patients: (i) disease flare (active-GPA, BVAS>6, n = 19), (ii) sustained remission (≥ 1-year prior enrollment, inactive-GPA, BVAS = 0, n = 18). 24 age-sex matched healthy subjects served as controls. Active-GPA patients were followed for 6 months and reevaluated during remission (early remission; n = 13). We analyzed subsets of Th-cells (flow cytometry), production of signature cytokines by in vitro stimulated lymphocytes, and broad spectrum of serum cytokines (Luminex). In all GPA patients we observed expansion of effector Th17 cells, and increased production of IL-17A by in vitro stimulated T cells, as compared to controls. Disease flare was characterized by marked reduction in Treg cells, whereas in sustained remission we showed expansion of both Treg and Th2 subset. Finally, analyzing the cytokine profile, we identified CCL23 and LIGHT, as potential biomarkers of active disease. We conclude that in GPA, expansion of Treg and Th2 lymphocytes in parallel to increased Th17 response is a characteristic feature of sustained remission. In contrast, Treg cells are markedly decreased in disease flare.

Relationship between different subpopulations of circulating CD4+ T lymphocytes and microvascular or systemic oxidative stress in humans

Background and objective: Different components of the immune system, including innate and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes – TREGs) may be involved in the development of hypertension, vascular injury and inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular oxidative stress. Our objective was to investigate possible relationships between T-lymphocyte subtypes and systemic and microvascular oxidative stress in a population of normotensive subjects and hypertensive patients.Patients and methods: In the present study we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. A peripheral blood sample was obtained before surgery for assessment of T lymphocyte subpopulations by flow cytometry and circulating indices of oxidative stress.Results: A significant direct correlation was observed between Th1 lymphocytes and reactive oxygen species (ROS) production (mainly in microvessels). Additionally, significant inverse correlations were observed between ROS and total TREGs, or TREGs subtypes. Significant correlations were detected between circulating indices of oxidative stress/inflammation and indices of microvascular morphology/Th1 and Th17 lymphocytes. In addition, a significant inverse correlation was detected between TREGs in subcutaneous small vessels and C reactive protein.Conclusions: Our data suggest that TREG lymphocytes may be protective against microvascular damage, probably because of their anti-oxidant properties, while Th1–Th17 lymphocytes seem to exert an opposite effect, confirming an involvement of adaptive immune system in microvascular damage.

Signal Transducer and Activator of Transcription 1 Plays a Pivotal Role in RET/PTC3 Oncogene-induced Expression of Indoleamine 2,3-Dioxygenase 1

Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors.

Relación entre linfocitos T reguladores (T regs) y anticuerpos anti-receptores de TSH (TRab) y el riesgo de cáncer de tiroides en enfermedad de Graves

In recent years the relationship between Graves’ disease (GD), TSH, TRAb and thyroid carcinoma has been studied. Research studies show a higher prevalence and aggressiveness of thyroid carcinoma in patients with GD, however other researchers refute these findings suggesting it's due to selection bias. Increasing evidence suggests a causal relationship between GD and the development of thyroid carcinoma, mainly because of the existence of TSI autoantibodies that could stimulate the focus of malignancy. It is believed that cytokines produced locally in patients with GD work alongside with TRAb regulating the aggressiveness of papillary thyroid carcinoma in these patients. Within the cells recruited by the tumor to elude the immune system we find Treg lymphocytes, which have been found to be increased in patients with GD, leading to a diminished immune response, creating a permissive environment for cell proliferation.Since this is a relatively new line of research, there is no consensus on the subject and its relevance for the treatment of patients with GD. The aim of this article is to show recent literature available on the subject.