Upregulation of GRAIL is associated with remission of ulcerative colitis

2008 ◽  
Vol 295 (1) ◽  
pp. G163-G169 ◽  
Author(s):  
Satoshi Egawa ◽  
Hideki Iijima ◽  
Shinichiro Shinzaki ◽  
Sachiko Nakajima ◽  
Jun Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Mrna Expression ◽  
Activity Index ◽  
Clinical Activity ◽  
E3 Ligases ◽  
T Cell Anergy ◽  
Before And After ◽  
Anergic T Cells ◽  
Active Disease

Abrogating tolerance against unidentified antigens is a critical step in the pathogenesis of ulcerative colitis (UC). T cell anergy, one of the main mechanisms of tolerance, has been shown to be induced by E3 ubiquitin ligases, such as gene related to anergy in lymphocytes (GRAIL), Itch, and c-Cbl in mice. However, it is not well known whether these E3 ligases play roles in human diseases. The pathophysiological role of the E3 ligases in patients with UC was investigated. At first, the expression of GRAIL, Itch, and c-Cbl in human anergic T cells was analyzed by quantitative RT-PCR and Western immunoblotting. Next, the mRNA expression of the E3 ligases was analyzed in peripheral CD4+ T cells of 20 patients with UC and 10 healthy volunteers (HV). mRNA expression was analyzed in patients with active UC before and after treatment with prednisolone and leukocytapheresis. Anergic human CD4+ T cells expressed significantly higher levels of GRAIL, Itch, and c-Cbl than nonanergic cells. GRAIL expression was significantly higher in patients with UC in remission than in patients with active disease and in HV ( P < 0.01). The level of GRAIL expression was also significantly increased in patients with active disease whose clinical activity index scores improved after treatment ( P < 0.05). There were no significant differences in Itch and c-Cbl expression among patients with active UC, patients with UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.

scholarly journals Fecal Calprotectin and Clinical Disease Activity in Pediatric Ulcerative Colitis

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Kaija-Leena Kolho ◽  
Dan Turner
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Outcome ◽  
Roc Curve ◽  
Clinical Remission ◽  
Activity Index ◽  
Fecal Calprotectin ◽  
Elisa Test ◽  
Clinical Activity ◽  
High Level ◽  
Active Disease

Objective. To explore fecal calprotectin levels in pediatric ulcerative colitis (UC) in relation with the validated clinical activity index PUCAI. Methods. This study included all 37 children (median age 14 years) with UC who had calprotectin measured (PhiCal ELISA Test) by the time of PUCAI assessment at the Children's Hospital of Helsinki in a total of 62 visits. Calprotectin values <100 μg/g of stool were considered as normal. The best cut-off value of each measure to predict 3-month clinical outcome was derived by maximizing sensitivity and specificity. Results. In clinically active disease (PUCAI ≥ 10), calprotectin was elevated in 29/32 patients (91% sensitivity). When in clinical remission, 26% (8/30) of the children had normal calprotectin but 7 (23%) had an exceedingly high level (>1000 μg/g). The best cut-off value for calprotectin for predicting poor outcome was 800 μg/g (sensitivity 73%, specificity 72%; area under the ROC curve being 0.71 (95%CI 0.57–0.85)) and for the PUCAI best cut-off values >10 (sensitivity 62%, specificity 64%; area under the ROC curve 0.714 (95%CI 0.58–0.85)). Conclusion. The clinical relevance of somewhat elevated calprotectin during clinical remission in pediatric UC is not known and, until further evidence accumulates, does not indicate therapy escalation.

scholarly journals Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells.

1996 ◽  
Vol 184 (1) ◽  
pp. 19-29 ◽  
Author(s):  
H Groux ◽  
M Bigler ◽  
J E de Vries ◽  
M G Roncarolo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
T Cell Anergy ◽  
Factor Alpha ◽  
Cell Anergy ◽  
Anergic T Cells ◽  
Macrophage Colony

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.

T1212 Upregulation of E3 Ubiquitin Ligases Related to T Cell Anergy in CD4+ T Cells Isolated from Patients with Ulcerative Colitis in Remission

2008 ◽  
Vol 134 (4) ◽  
pp. A-508
Author(s):  
Satoshi Egawa ◽  
Hideki Iijima ◽  
Shinichiro Shinzaki ◽  
Sachiko Nakajima ◽  
Jumpei Kondo ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
T Cell Anergy ◽  
Cell Anergy

scholarly journals P187 The significance of netrin-1 level in the clinical activity of ulcerative colitis, its association between TNF-α and IL-6

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S232-S232
Author(s):  
H Korkmaz ◽  
K Fidan
Keyword(s):  
Ulcerative Colitis ◽  
Proinflammatory Cytokines ◽  
Activity Index ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Clinical Activity ◽  
Tnf Α ◽  
Significant Difference ◽  
And Control ◽  
Control Study

Abstract Background In this study, we investigated the importance of netrin-1 levels in ulcerative colitis (UC) in clinical activity of the disease, and its association with other proinflammatory cytokines IL-6 and TNF-α. Methods This study is a type of case–control study. Sixty-seven patients with UC (36 of them activation, 31 of remission) and 50 healthy controls were included in the study. UC patients; ‘Truelove Witts clinical activity index by remission (n = 31), mild activation (n = 21), moderate activation (n = 6) and severe activation (n = 9) were divided into groups. Netrin, IL-6 and TNF-α measurements in plasma samples were performed using enzyme-linked immunosorbent assay kit. Results Between the patient group and the control group; there was a statistically significant difference between netrin-1, IL-6, TNF-α, neutrophil, platelet (p &lt; 0.05 for all). The plasma netrin-1 mean of UC with severe activation group (139.21 ± 48.09 pg/ml) was statistically significantly higher than that of the mild activation (p = 0,037), remission group (p = 0,001) and control group(p = 0,011). The plasma netrin-1 mean of UC with moderate activation group was statistically significantly higher than that of the mild activation(p = 0,045) and remission group(p = 0,004). Conclusion Our results reveal that plasma netrin-1 levels have been shown to be associated with UC activation, similar to proinflammatory cytokines such as TNF-α and IL-6, in UC.

Retinoic Acid Is Elevated in the Mucosa of Patients With Active Ulcerative Colitis and Displays a Proinflammatory Role by Augmenting IL-17 and IFNγ Production

2020 ◽  
Vol 27 (1) ◽  
pp. 74-83 ◽  
Author(s):  
Ritika Rampal ◽  
Nahidul Wari ◽  
Amit Kumar Singh ◽  
Ujjwalkumar Das ◽  
Sawan Bopanna ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Retinoic Acid ◽  
Crucial Role ◽  
Intestinal Inflammation ◽  
Γδ T Cells ◽  
Inflammatory Conditions ◽  
Invariant T Cells ◽  
Active Disease

Abstract Background All-trans retinoic acid (RA) plays a crucial role in promoting Foxp3+ Treg generation while reciprocally inhibiting Th1/Th17 generation. Our previous research highlighted that in the face of inflammatory conditions, RA plays a contrary role where it aggravates intestinal inflammation by promoting interferon (IFN) γ and interleukin (IL)-17 differentiation in vitro. Methods In this study we translated our in vitro results into a clinical setting where we estimated mucosal and serum RA levels along with the immunophenotypic profile (IL-17, IFNγ, Foxp3, IL-10) in adaptive (CD4, CD8) and innate-like T cells (mucosal associated invariant T cells and γδ T cells) in patients with ulcerative colitis in remission or with active inflammation. Results This is the first study to estimate RA levels in the human gut and shows that patients with active disease had increased mucosal RA levels as compared with patients in remission (4.0 vs 2.5 ng/mL; P &lt; 0.01) and control patients (3.4 vs 0.8 ng/mL; P &lt; 0.0001). This effect was accompanied by significantly elevated IL-17 and IFNγ in tissue CD4+, CD8+, mucosal associated invariant T+ cells, and γδ + T cells. Moreover, the raised RA levels in patients with active disease showed a positive correlation with proinflammatory cytokines (IL-17, IFNγ) and a negative correlation with IL-10. We also found that RA negatively correlated with IL-9, thereby reinstating our previous finding that RA inhibits Th9 differentiation. Conclusions These data confirm our previous in vitro results that in the presence of inflammation, RA plays a crucial role in maintaining gut inflammation by upregulating proinflammatory markers.

scholarly journals P807 UCEIS is associated with PRO2, partial Mayo and SCCAI remission in UC: preliminary results from a prospective study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S631-S631
Author(s):  
P A Golovics ◽  
L Gonczi ◽  
J Reinglass ◽  
C Verdon ◽  
W Afif ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Remission ◽  
Roc Analysis ◽  
Clinical Decision Making ◽  
Activity Index ◽  
Operating Characteristics ◽  
Faecal Calprotectin ◽  
Patient Reported ◽  
Index Of Severity ◽  
Active Disease

Abstract Background Optimal management of patients with ulcerative colitis (UC) requires the accurate assessment of disease activity. Endoscopic evaluation is considered the gold standard approach, but it is invasive. We aimed to determine the operating characteristics of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), to quantify the cut off most closely correlated with clinical remission or activity and determine agreement with the Mayo endoscopic subscore (MES), Baron score, clinical scores and biomarkers. Methods 136 patients were included prospectively (age: 48 (IQR38-61) years, duration 12 (4–19)years, 63 females, 53.7% extensive disease, 40.4% on biologicals) at the time of the colonoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Mayo endoscopic subscore (MES), Baron scores were calculated, as well as the2 item patient reported outcome (PRO), partial MAYO, Simple Clinical Colitis Activity Index (SCCAI). CRP and faecal calprotectin (FCAL) was available in 58.1 and 33.8% of patients. 20.7% had clinical flare, treatment was escalated in 17.8% of patients. ROC analysis and K-statistics were performed and Spearman’s correlation was calculated. Results UCEIS was strongly associated to PRO2 SF (AUC:0.866), RBS (AUC:0.921), PRO2 combined remission (AUC:0.905), partial MAYO (AUC:0.956) and SCCAI (AUC:0.907) remission in a ROC analysis. A UCEIS of ≤3 was identified as the best cut-off to identify RBS subscore of 0, or total PRO2 remission (RBS 0 and SF ≤1), partial MAYO (≤2) and SCCAI (≤2.5) remission, while a UCEIS≥4 identified active disease frequently needing change in medical therapy. A moderate agreement was found between UCEIS and MES (K=0.451) or Baron (K=0.499) scores. Correlation between FCAL and UCEIS (coeff:0.743, p &lt; 0.0001) was strong, while modest only with CRP (coeff:0.333, p = 0.01). Conclusion A UCEIS was strongly associated with clinical remission defined as PRO2, SF, RBS, partial Mayo or SCCAI with best agreement with RBS and partial Mayo remission. A UCEIS of ≤3 was identified as a cut-off for quiescent disease, while a UCEIS≥4 identified active disease, which can support clinical decision-making based on endoscopic findings. Agreement between UCEIS and FCAL was strong, while agreement with UCEIS and MES/Baron scores was moderate.

WT1-Peptide Vaccination Shows High Immunogenicity and Clinical Activity in Patients with Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 406-406 ◽  
Author(s):  
Keilholz Ulrich ◽  
Carmen Scheibenbogen ◽  
Anne Letsch ◽  
Anne Marie Asemissen ◽  
Wolf Karsten Hofmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Clinical Outcome ◽  
Peripheral Blood ◽  
Great Promise ◽  
Clinical Activity ◽  
Peptide Vaccination ◽  
Before And After ◽  
Disease Stabilization

Abstract BACKGROUND: The transcription factor Wilms tumor protein 1 (WT1) holds great promise for immunotherapy of leukemia. WT1 is strongly expressed in the majority of leukemic blasts, is essential for blast proliferation, and is spontaneously immunogenic. METHODS: In the present phase II trial, 12 HLA-A2+ patients with AML without curative treatment option, were vaccinated with WT1.126–134 peptide mixed with adjuvant KLH as T-helper protein and GM-CSF 4 times bi-weekly, then monthly. RESULTS: Patients characteristics, immune responses and clinical outcome are shown in table 1. Patient characteristics, immunologic response, and clinical outcome Pat FAB/caryotype previous chemotherapy disease status at study onset no. of vaccinations clinical outcome WT1Tetr+ T cells in PB after vaccination WT1Tetr+ T cells in BM after vaccination *PB, peripheral blood; BM, bone marrow; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease. 1 M4 yes 2.PR 15 CR 12 months 0.49% 0.87% 2 M2 11q23 yes 1.CR 18 cCR 30+ months 0.43% 0.91% 3 M2 no PD 4 SD 3 months 0.42% 0.80% 4 M6 yes PD 4 PD neg. neg. 5 M2 yes 1.PR 6 PD 0.37% 0.51% 6 M1 yes 2. PR 9 PD 0.43% 0.40% 7 M2 yes 2.PR 9 PD 2.00% 1.36% 8 M7 yes PD 4 PD neg. neg. 9 M5b yes 2.CR 12 cCR 8+ months 0.44% 0.33% 10 sAML from MDS no PD 12 SD 8 months 0.23% 0.13% 11 sAML from MPS no PD 12 SD 9+ months 0.22% 0.53% 12 M4 no PD 8 SD 3 months 1.11% 1.35% WT1-specific T cells could be detected in 3 patients before vaccination. An induction or enhancement of a T cell response against WT1 was observed in 10 of 12 patients after 2 – 6 vaccinations ranging from 0.22 to 2.00% (median 0.43%) in peripheral blood and from 0.33 to 1.36% (median 0.80%) in bone marrow as analysed by tetramer and cytokine staining. At study onset 6 patients had progressive AML (PD) with 40 – 90% marrow blasts, 4 patients partial remission (PR) following chemotherapy and two patients complete remission (CR) at high risk for relapse. Four of the 6 patients with progressive AML had disease stabilization for 3, 3, 8 and 9 months, which is ongoing in the latter patient. Disease stabilization was accompanied by a decrease/normalization of peripheral blasts in two patients and a &gt;50% decrease in RBC transfusion requirements in a patient with AML evolved from MDS. One patient with PR at study onset had an early relapse and then achieved CR for 12 months (patient 1). Both patients vaccinated in CR are in continuous hematological CR (cCR) for 8+ and 30+ months (patient 2 and 9). The remaining 5 patients had PD after 4 – 9 vaccinations. Bone marrow WT1 RNA levels as molecular disease marker paralleled the clinical course as they decreased 1 – 2 logs in the 3 patients with CR or cCR after 6 vaccinations (Fig. 1A), stabilized or decreased in all 4 patients with SD (Fig. 1B), and increased 1 – 2 logs in 4 of the 5 patients with PD (Fig. 1B). No significant toxic effects were observed. CONCLUSION: WT1 peptide vaccination can efficiently induce a specific immune response and has clinical activity in the absence of significant toxicity. These results warrant further studies of WT1 vaccination in AML patients at high risk for relapse. Fig. 1 WT1 levels in bone marrow before and after 6 vaccinations in patients with CR or cCR (A), SD (B) or PD (C) after vaccination. Fig. 1. WT1 levels in bone marrow before and after 6 vaccinations in patients with CR or cCR (A), SD (B) or PD (C) after vaccination.

Higher Frequency of Peripheral Blood Interleukin 21 Positive Follicular Helper T Cells in Patients with Ankylosing Spondylitis

2013 ◽  
Vol 40 (12) ◽  
pp. 2029-2037 ◽  
Author(s):  
Fei Xiao ◽  
Hai-Yu Zhang ◽  
Yi-Jun Liu ◽  
Ding Zhao ◽  
Yu-Xing Shan ◽  
...  
Keyword(s):  
T Cells ◽  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Activity Index ◽  
Disease Activity Index ◽  
Inducible Costimulator ◽  
Before And After ◽  
Interleukin 21

Objective.The role of follicular Th (TFH) cells remains unclear in the pathogenesis of ankylosing spondylitis (AS). Our study examined the frequency of different subsets of circulating CXCR5+CD4+ T cells in patients with AS before and after receiving therapy.Methods.Percentages of peripheral blood inducible costimulator (ICOS)+, programmed death 1 (PD-1)+, and interleukin 21 (IL-21)+ CXCR5+CD4+ T cells in 26 patients with AS and 12 healthy controls (HC) were examined by flow cytometry, and the disease activity of individual patients was measured by Bath AS Disease Activity Index (BASDAI). The concentrations of serum IL-21, IgG, IgA, IgM, and C-reactive protein (CRP) were examined and the values of erythrocyte sedimentation rate (ESR) were measured. The potential association among these measures was analyzed.Results.In comparison with that in HC, significantly increased percentages of CXCR5+CD4+, CXCR5+CD4+PD-1+, and CXCR5+CD4+IL-21+, but not CXCR5+CD4+ICOS+ and PD-1+ICOS+CXCR5+CD4+ T cells, and elevated concentrations of serum IL-21 were detected in patients with AS (p = 0.001, p = 0.012, p < 0.001, p = 0.233, p = 0.216, p < 0.001, respectively). Treatment with meloxicam, thalidomide, and etanercept for 1 month significantly reduced percentages of IL-21+CXCR5+CD4+ T cells and concentrations of serum IL-21 (p < 0.001, p < 0.001, respectively), accompanied by significantly minimized disease activity in drug responders, but not in the drug nonresponders. Further, percentages of IL-21+CXCR5+CD4+ T cells were positively correlated with BASDAI in patients (r = 0.6, p = 0.0012) and in the drug-responders 1 month after treatment (r = 0.68, p = 0.005), while the percentages of PD-1+CXCR5+CD4+ T cells were negatively correlated with BASDAI (r = −0.58, p = 0.0018).Conclusion.These data suggest that IL-21+CXCR5+CD4+ T cells may be associated with development of AS and that the frequency of IL-21+CXCR5+CD4+ T cells may be a biomarker for evaluation of disease activity and drug responses in patients with AS, particularly in drug-responding patients.

scholarly journals PAG-Associated FynT Regulates Calcium Signaling and Promotes Anergy in T Lymphocytes

2007 ◽  
Vol 27 (5) ◽  
pp. 1960-1973 ◽  
Author(s):  
Dominique Davidson ◽  
Burkhart Schraven ◽  
André Veillette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Anergic T Cells ◽  
Selective Enhancement

ABSTRACT Phosphoprotein associated with glycolipid-enriched membranes (PAG), also named Csk-binding protein (Cbp), is a transmembrane adaptor associated with lipid rafts. It is phosphorylated on multiple tyrosines located in the cytoplasmic domain. One tyrosine, tyrosine 314 (Y314) in the mouse, interacts with Csk, a protein tyrosine kinase that negatively regulates Src kinases. This interaction enables PAG to inhibit T-cell antigen receptor (TCR)-mediated T-cell activation. PAG also associates with the Src-related kinase FynT. Genetic studies indicated that FynT was required for PAG tyrosine phosphorylation and binding of PAG to Csk in T cells. Herein, we investigated the function and regulation of PAG-associated FynT. Our data showed that PAG was constitutively associated with FynT in unstimulated T cells and that this association was rapidly lost in response to TCR stimulation. Dissociation of the PAG-FynT complex preceded PAG dephosphorylation and PAG-Csk dissociation after TCR engagement. Interestingly, in anergic T cells, the association of PAG with FynT, but not Csk, was increased. Analyses of PAG mutants provided evidence that PAG interacted with FynT by way of tyrosines other than Y314. Enforced expression of a PAG variant interacting with FynT, but not Csk, caused a selective enhancement of TCR-triggered calcium fluxes in normal T cells. Furthermore, it promoted T-cell anergy. Both effects were absent in mice lacking FynT, implying that the effects were mediated by PAG-associated FynT. Hence, besides enabling PAG tyrosine phosphorylation and the PAG-Csk interaction, PAG-associated FynT can stimulate calcium signals and favor T-cell anergy. These data improve our comprehension of the function of PAG in T cells. They also further implicate FynT in T-cell anergy.

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