Preserved Th2 lymphocytes improve prognosis of diabetic patients undergoing TAVR

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Hoffmann ◽  
A Berkowitsch ◽  
S Mas-Peiro ◽  
F Boeckling ◽  
T Rasper ◽  
...  
Keyword(s):  
T Cell ◽  
Aortic Stenosis ◽  
Cell Polarization ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Diabetic Patients ◽  
Th1 Cells ◽  
Cell Counts ◽  
T Cell Polarization ◽  
Sts Score

Abstract Introduction Previous studies have shown that presence of diabetes (DM) worsens outcome of patients after transfemoral aortic valve (TAVR). DM has been associated with pathological T-lymphocyte (T-cell) polarization, marked by decreased anti-inflammatory Th2 cells and increased pro-inflammatory Th1 cells. However, the risk-modulatory impact of T-cell polarization in diabetic patients with severe aortic stenosis has not been shown thus far. In this study we assessed the role of T-cell subsets in diabetic patients undergoing TAVR. Methods and results A total of 129 patients (76% male, median age [IQR]: 83 years [79–86]) admitted for TAVR at the University Clinic Frankfurt were enrolled. The patients were evaluated using classical risk scores and the Th1/Th2 T-cell polarization was assessed using flow cytometry. The endpoint of the study was all-cause death. Kaplan-Meier survival, ROC curve analysis and Mann-Whitney-U-Test were used in statistical analysis. The differences were considered significant by error probability p<0.05. Twenty-six patients died within follow up of 274 (188–367) days. The conventional risk parameters were distributed as follows: STS score: 3.45 (2.47–4.97), LVEF: 60% (45–65), CRP: 0.33 mg/dl (0.15–0.79), hsTropT: 24.5 pg/ml (16.5–40.0), IL6: 6.7 pg/ml (4.1–12.2), Hb: 12.3 g/dl (11.00–13,75), Creatinine: 1.15 mg/dl (0.93–1.54), Th1 cells = 79.88 cells/μl (55.69–122.16), Th2 cells: 25.31 cells/μl (19.69–38.33), NT-proBNP: 2033 pg/ml (1076–5531). All these parameters were associated with mortality. Hence, only Hb (AUC=0.761), NT-proBNP (AUC=0.726), Th2 cells (AUC=0.712) and STS score (AUC=0.737) provided AUC>0.7. Diabetes was revealed to be significantly associated with mortality in patients with and without DM (15/48 (31%) vs. 11/81 (14%), respectively, P=0.019). There were no significant differences in the counts of Th-cell subsets between diabetic and non-diabetic patients (Th1 (90.95 (62.41–154.22) vs 76.36 (53.16–100.49), P=0.072); Th2 (29.18 (20.13–43.77) vs 24.74 (20.27- 35.11), p=0.245), for DM and non-DM respectively). However, the survival rate in patients with DM and Th2 cell counts higher than or equal to the calculated optimal cut-off of 24.3 cells/μl was comparable with patients without DM (25/28 (89%) vs. 36/38 (95%), p=0.453). In contrast, diabetic patients with reduced Th2 cells (<24.3 cells/μl) were much more likely to die (10/15 (67%) vs. 8/34 (24%), p=0.003, patients with DM and without, respectively). Conclusion Our results show for the first time a risk-modulatory impact of T-cell immunity in diabetic patients with severe degenerative aortic stenosis. Reduced Th2 cells are strongly associated with mortality in patients considered for TAVR and significantly deteriorate prognosis in patients with concomitant diabetes. Funding Acknowledgement Type of funding source: None

scholarly journals Rapid Development of Th2 Activity During T Cell Priming

2003 ◽  
Vol 10 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Adam F. Cunningham ◽  
Kai-Michael Toellner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rapid Development ◽  
Critical Role ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th 1 ◽  
Th1 And Th2

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 inductionin vitroindicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarizationin vivocannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones.

P930Inflammatory leukocyte phenotypes are associated with increased mortality after transfemoral transcatheter aortic valve implantation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Hoffmann ◽  
S Mas-Peiro ◽  
F Boeckling ◽  
T Rasper ◽  
A Berkowitsch ◽  
...  
Keyword(s):  
T Cell ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Risk Stratification ◽  
Transcatheter Aortic Valve Implantation ◽  
T Cell Subsets ◽  
Transcatheter Aortic Valve ◽  
Sts Score ◽  
Aortic Valve Implantation ◽  
Valve Implantation

Abstract Background Systemic inflammatory response syndrome (SIRS) was shown to be a strong predictor of mortality in patients undergoing transcatheter aortic valve implantation (TAVI). However, given the rather non-specific nature of the SIRS criteria and their limited applicability in the modern era of TAVI, including lower periprocedural complication rates and shorter hospitalization periods in experienced competence centers, there is a need for defining novel prognostic inflammatory signatures for improved patient risk stratification. Thus, the objective of the present study was to characterize and assess the prognostic relevance of circulating leukocyte subsets, including phenotypical heterogeneity of monocytes and effector T cells, before and at various times after transfemoral TAVI. Methods and results 129 consecutive patients (59% male, mean age 82.3±5.6 years) with severe symptomatic aortic stenosis (Pmean 44.2±17mmHg), and high or prohibitive operative risk (mean EuroSCORE II 5.9; STS score 4.1) admitted to our clinic for TAVI were included into the study. Peripheral blood samples were obtained pre-procedurally (baseline, BL), directly after the intervention, and at 24h and 3 days after TAVI, and analyzed for inflammatory and cardiac biomarkers, including hs-CRP, IL-6, hs-TropT, and NT-proBNP. Differential myeloid and T-cell subset (Th1, Th2, Th17, Th1/Th17, Th22, Tregs) distribution and kinetics were analyzed using multiparameter flow cytometry. Neutrophil (P<0.001 vs. BL) as well as classical and intermediate monocyte counts were significantly elevated at 24h (both p<0.0001 vs. BL), whereas non-classical monocytosis developed 3 days after TAVI (P<0.0001 vs. BL). Among CD4+ T-cell subsets, the percentage of Tregs and Th17 significantly increased (both P<0.0001 at 24h vs. BL) after valve implantation. Remarkably, these changes were independent on the valve type (balloon- vs. self-expandable) and no significant effects of predilatation were observed (p>0.05 for all cell subsets). Univariate analysis showed that elevated levels of NT-proBNP (HR: 3.4, 95% CI: 1.7–6.8; P=0.0005), hsCRP (HR: 1.4, 95% CI: 1.2–1.7; P=0.0003), and IL-6 (HR: 1.0, 95% CI: 1.0–1.03; P=0.0007), lower counts of Th2 cells (HR: 0.94, 95% CI: 0.90–0.94; P=0.0045), as well as increased percentages of Th17 cells (HR: 1.2, 95% CI: 1.0–1.4; P=0.023), and of non-classical monocytes (HR=1.019, 95% CI: 1.001–1.039; P=0.049) were independently associated with 12-month all-cause mortality. When included in the regression model with STS score, these inflammatory biomarkers provided higher area under ROC curve and category-free net reclassification improvementof 59% at 1 year (P=0.0001). ROC curves inflammation markers add STS Conclusions Our findings demonstrate for the first time an association of inflammatory leukocyte phenotypes with increased mortality after TAVI. Specific monocytic and T-cell signatures might therefore provide novel additive biomarkers to improve individual risk stratification in patients with severe aortic stenosis.

scholarly journals Leptin: A Critical Regulator of CD4+ T-cell Polarization in Vitro and in Vivo

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Arvind Batra ◽  
Besir Okur ◽  
Rainer Glauben ◽  
Ulrike Erben ◽  
Jakob Ihbe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Regulatory Function ◽  
Wild Type ◽  
T Helper ◽  
T Cell Polarization

Abstract Besides being mandatory in the metabolic system, adipokines like leptin directly affect immunity. Leptin was found to be necessary in T helper 1 (Th1)-dependent inflammatory processes, whereas effects on Th2 cells are rarely understood. Here, we focused on leptin in T-helper cell polarization and in Th2-mediated intestinal inflammation in vivo. The induction of cytokine-producing Th1 or Th2 cells from naive CD4+ T cells under polarizing conditions in vitro was generally decreased in cells from leptin-deficient ob/ob mice compared with wild-type mice. To explore the in vivo relevance of leptin in Th2-mediated inflammation, the model of oxazolone-induced colitis was employed in wild-type, ob/ob, and leptin-reconstituted ob/ob mice. Ob/ob mice were protected, whereas wild-type and leptin-reconstituted ob/ob mice developed colitis. The disease severity went in parallel with local production of the Th2 cytokine IL-13. A possible explanation for the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3, in naive ob/ob T cells. In conclusion, these results support the regulatory function of the adipokine leptin within T-cell polarization and thus in the acquired immune system and support the concept that there is a close interaction with the endocrine system.

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis

Rheumatology ◽  
2020 ◽  
Author(s):  
Jonathan London ◽  
Nicolas Dumoitier ◽  
Sébastien Lofek ◽  
Jérémie Dion ◽  
Benjamin Chaigne ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Polarization ◽  
Receptor Expression ◽  
T Cell Subsets ◽  
Fluorescence Intensity Ratio ◽  
Cell Compartments ◽  
B Cell Activating Factor ◽  
T Cell Polarization

Abstract Objectives To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). Results GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21– B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P &lt; 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P &lt; 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). Conclusion Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

scholarly journals Fructo-Oligosaccharides Modify Human DC Maturation and Peanut-Induced Autologous T-Cell Response of Allergic Patients In Vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Simone M. Hayen ◽  
André C. Knulst ◽  
Johan Garssen ◽  
Henny G. Otten ◽  
Linette E. M. Willemsen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cell Response ◽  
Cell Polarization ◽  
T Cell Response ◽  
Th2 Cells ◽  
Cell Assay ◽  
T Cell Polarization ◽  
Dc Maturation

BackgroundDendritic cells (DCs) play an important role in antigen presentation, and are an interesting target for immune-modulation in allergies. Short- and long-chain fructo-oligosaccharides (scFOS/lcFOS, FF) have immunomodulatory capacities, and may influence the outcome of DC antigen presentation.ObjectiveThis study investigated the effect of FF during DC maturation and allergen presentation using cells of peanut-allergic patients in an autologous DC-T cell assay.MethodsCD14+ and CD4+ T cells were isolated from peanut-allergic patients. CD14+ monocytes were differentiated into immature DCs (imDCs), and matured (matDCs) in the presence or absence of crude peanut-extract (CPE) and/or FF, and co-cultured in an autologous DC-T cell assay. T cell polarization, proliferation and cytokine production were measured.ResultsExpression of maturation surface molecule markers on matDCs was not affected by CPE and/or FF. By contrast, the IL-10 secretion by matDCs increased compared to imDCs, upon exposure to CPE and FF compared to CPE alone. Also the IP-10 secretion increased in CPE/FF-matDCs compared to imDC. CPE-matDCs enhanced IL-13 release in the DC-T-cell assay and Treg polarization in presence or absence of FF. CPE/FF-DCs tended to increase the Treg/Th1 and Treg/Th2 ratios compared to matDCs. The proliferation of both Treg and Th2 cells tended to increase when T cells were co-cultured with CPE-matDCs compared to matDCs, which became significant when CPE-matDCs were also exposed to FF and a same tendency was shown for Th1 proliferation.ConclusionOnly in the presence of FF, CPE-matDCs produced increased regulatory and Th1-related mediators. CPE-matDCs modified T cell polarization and proliferation, and additional exposure to FF tended to enhance Treg/Th2 and Treg/Th1 ratios instructed by CPE/FF-matDCs. However this effect was not strong enough to suppress CPE-matDCs induced IL-13 release by Th-cells. This indicates the ability of FF to modify DC maturation in the presence of an allergen supporting a more Treg/Th1 prone direction of the successive allergen specific Th2 cell response.

scholarly journals Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Mahmoud Youssef ◽  
Eslam Abd El-Fattah ◽  
Amir Abdelhamid ◽  
Hanan Eissa ◽  
Eman El-Ahwany ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cell ◽  
Activity Index ◽  
Damage Index ◽  
Cell Polarization ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Ampk Phosphorylation ◽  
T Cell Polarization ◽  
Anti Inflammatory

Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.

scholarly journals Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 250-257 ◽  
Author(s):  
G Del Prete ◽  
M De Carli ◽  
RM Lammel ◽  
MM D'Elios ◽  
KC Daniel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tissue Factor ◽  
Procoagulant Activity ◽  
T Cell Subsets ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Human Monocytes ◽  
Ifn Gamma

The role of T-cell subsets in the induction of tissue factor (TF) production by human monocytes in vitro was investigated. Mitogen stimulation enabled both unfractionated T cells and their CD4+ or CD8+ subsets to promote procoagulant activity (PCA). After mitogen or antigen activation, all seven T-cell clones with Th1 cytokine profile, but none of seven Th2 clones, induced TF production and PCA. T-cell blasts from four Th1 activated clones were fixed with paraformaldehyde and added to monocytes in the presence of medium alone or their supernatants. Addition of either fixed Th1 cells or their supernatants induced low TF production (0.2 to 0.6 ng/mL), whereas addition of both resulted in much higher TF synthesis (1.8 to 3.4 ng/mL). Among Th1-type cytokines, only interferon-gamma (IFN-gamma) induced minimal TF production (0.1 to 0.4 ng/mL). No TF synthesis was induced by activated and fixed Th2 cells and/or their supernatants, whereas combined addition of fixed Th2 cells and Th1 supernatants or IFN-gamma induced noticeable TF production. The addition of either anti-IFN-gamma antibody or Th2 supernatants to monocytes stimulated with activated and fixed Th1 cells plus their supernatant resulted in a dose-dependent inhibition of TF synthesis, which was partially restored by neutralization of interleukin-4 (IL-4) or IL-10. Addition of recombinant IL-4, IL-13, or IL-10, but not IL-5, inhibited the Th1- induced TF production by monocytes. Data indicate that both CD8+ and CD4+ Th1, but not Th2, T cells can help TF production and PCA. Both cell-to-cell contact with activated T cells and Th1-type cytokines, in particular IFN-gamma, are required for optimal TF synthesis, whereas Th2-derived cytokines (IL-4, IL-13, and IL-10) are inhibitory. This may be of potential interest for future therapeutic strategies.

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