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1.
Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response.
Golebski, K, Layhadi, JA, Sahiner, U, Steveling-Klein, EH, Lenormand, MM, Li, RCY, Bal, SM, Heesters, BA, Vilà-Nadal, G, Hunewald, O, et al
Immunity. 2021;(2):291-307.e7
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Abstract
The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1- ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.
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High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician's choice-in the EMBRACE study.
Miyoshi, Y, Yoshimura, Y, Saito, K, Muramoto, K, Sugawara, M, Alexis, K, Nomoto, K, Nakamura, S, Saeki, T, Watanabe, J, et al
Breast cancer (Tokyo, Japan). 2020;(4):706-715
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Abstract
BACKGROUND Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). METHODS The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician's choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. RESULTS Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437-0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800-1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. DISCUSSION This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures. TRIAL REGISTRATION www.ClinicalTrials.gov code: NCT00388726.
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Preceding exercise and postprandial hypertriglyceridemia: effects on lymphocyte cell DNA damage and vascular inflammation.
Brown, M, McClean, CM, Davison, GW, Brown, JCW, Murphy, MH
Lipids in health and disease. 2019;(1):125
Abstract
BACKGROUND Exercise has proved effective in attenuating the unfavourable response normally associated with postprandial hypertriglyceridemia (PHTG) and accompanying oxidative stress. Yet, the acute effects of prior exercise and PHTG on DNA damage remains unknown. The purpose of this study was to examine if walking alters PHTG-induced oxidative damage and the interrelated inflammatory mechanisms. METHODS Twelve apparently healthy, recreationally active, male participants (22.4 ± 4.1 years; 179.2 ± 6 cm; 84.2 ± 14.7 kg; 51.3 ± 8.6 ml·kg- 1·min- 1) completed a randomised, crossover study consisting of two trials: (1) a high-fat meal alone (resting control) or (2) a high-fat meal immediately following 1 h of moderate exercise (65% maximal heart rate). Venous blood samples were collected at baseline, immediately post-exercise or rest, as well as at 2, 4 and 6 h post-meal. Biomarkers of oxidative damage (DNA single-strand breaks, lipid peroxidation and free radical metabolism) and inflammation were determined using conventional biochemistry techniques. RESULTS DNA damage, lipid peroxidation, free radical metabolism and triglycerides increased postprandially (main effect for time, p < 0.05), regardless of completing 1 h of preceding moderate intensity exercise. Plasma antioxidants (α-tocopherol and γ-tocopherol) also mobilised in response to the high-fat meal (main effect for time, p < 0.05), but no changes were detected for retinol-binding protein-4. CONCLUSION The ingestion of a high fat meal induces postprandial oxidative stress, inflammation and a rise in DNA damage that remains unaltered by one hour of preceding exercise.
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Acute glutamine ingestion modulates lymphocytic responses to exhaustive exercise in the heat.
Zheng, C, Chen, XK, Zhou, Y
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2018;(3):213-220
Abstract
The purpose of this study was to determine if acute intake of glutamine modulates homeostatic, hematologic, immune, and inflammatory responses to exhaustive exercise in the heat. Thirteen healthy, untrained young men participated in this randomized, double-blind, placebo-controlled, crossover study. They served as their own control and completed 2 trials of treadmill exercise at 40% maximal oxygen uptake to exhaustion in a hot environment (temperature, 38.0 ± 1.0 °C; relative humidity, 60.0% ± 5.0%; oxygen, 20.8%) following placebo (PLA) and glutamine (GLN) consumption. Heart rate, gastrointestinal temperature, forehead temperature, the rating of perceived exertion, and body weight were measured. Blood samples were collected before and after exercise. After exhaustive exercise in the heat (PLA vs. GLN: 42.0 ± 9.5 vs. 39.6 ± 7.8 min, p > 0.05), significant changes in homeostatic, hematologic, and immune parameters (elevated natural killer (NK) cells and neutrophils, and reduced CD4+/CD8+ ratio and CD19+ lymphocytes) were found in the control group owing to the time effect (p < 0.05). Moreover, a condition × time interaction effect was observed for the absolute count of CD3+ (F = 4.26, p < 0.05) and CD3+CD8+ T lymphocytes (F = 4.27, p < 0.05), which were elevated following acute glutamine intervention. While a potential interaction effect was also observed for the absolute count of CD3+CD4+ T lymphocytes (F = 3.21, p = 0.08), no condition or interaction effects were found for any other outcome measures. The results of this study suggest that acute glutamine ingestion evokes CD3+ and CD3+CD8+ T lymphocytosis but does not modulate neutrophil and NK cell leukocytosis and immune disturbances after exhaustive exercise in the heat.
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Effects of normoxic and hypoxic exercise regimens on lymphocyte apoptosis induced by oxidative stress in sedentary males.
Wang, JS, Chen, YC, Chen, WL, Lin, CP
European journal of applied physiology. 2017;(12):2445-2455
Abstract
PURPOSE Oxidative stress-induced lymphocyte apoptosis is linked to hypoxemic individuals suffering from cardiopulmonary disorders or exposed to hypoxic environments. What kind of the exercise strategy under hypoxic condition improves exercise performance and simultaneously minimizes lymphocyte dysfunction caused by oxidative stress has not yet been established. This study elucidates how various exercises regimens with/without hypoxia affect lymphocyte apoptosis induced by oxidative stress. METHODS A total of 60 sedentary males were randomly divided into five groups. Each group (n = 12) received one of the five interventions: hypoxic-absolute exercise (HAT, 50%W max under 15%O2), hypoxic-relative exercise (HRT, 50% heart rate reserve under 15%O2), normoxic exercise (NT, 50%W max under 21%O2), hypoxic control (HC, resting under 15%O2), or normoxic control (NC, resting under 21%O2) for 30 min/day, 5 days/week for 4 weeks. RESULTS Before the intervention, the graded exercise test (GXT, progressive exercise up to VO2max) decreased the surface thiol level on lymphocytes and subsequently augmented the extents of H2O2-induced mitochondria transmembrane potential (MTP) diminishing, caspase 3/8/9 activations, and phosphotidyl serine (PS) exposure in lymphocytes. However, 4 weeks of NT, HRT, or HAT reduced the extents of surface thiol decreasing on lymphocytes and H2O2-induced MTP diminishing, caspase 3/8/9 activations, and PS exposure in lymphocytes following GXT. Moreover, the HAT group exhibited greater improvements in pulmonary ventilation and VO2max than either NT or HRT group did. CONCLUSIONS Exercise training with/without hypoxic exposure effectively alleviates lymphocyte apoptosis induced by oxidative stress following strenuous exercise. However, the HAT is superior to the NT or HRT for enhancing aerobic capacity.
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Double-Blind Randomized Clinical Trial: Gluten versus Placebo Rechallenge in Patients with Lymphocytic Enteritis and Suspected Celiac Disease.
Rosinach, M, Fernández-Bañares, F, Carrasco, A, Ibarra, M, Temiño, R, Salas, A, Esteve, M
PloS one. 2016;(7):e0157879
Abstract
BACKGROUND The role of gluten as a trigger of symptoms in non-coeliac gluten sensitivity has been questioned. AIM: To demonstrate that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for non-coeliac gluten sensitivity (NCGS), which presented with lymphocytic enteritis, positive celiac genetics and negative celiac serology. METHODS Double-blind randomized clinical trial of gluten vs placebo rechallenge. INCLUSION CRITERIA >18 years of age, HLA-DQ2/8+, negative coeliac serology and gluten-dependent lymphocytic enteritis, and GI symptoms, with clinical and histological remission at inclusion. Eighteen patients were randomised: 11 gluten (20 g/day) and 7 placebo. Clinical symptoms, quality of life (GIQLI), and presence of gamma/delta+ cells and transglutaminase deposits were evaluated. RESULTS 91% of patients had clinical relapse during gluten challenge versus 28.5% after placebo (p = 0.01). Clinical scores and GIQLI worsened after gluten but not after placebo (p<0.01). The presence of coeliac tissue markers at baseline biopsy on a gluten-free diet allowed classifying 9 out of the 18 (50%) patients as having probable 'coeliac lite' disease. CONCLUSION This proof-of-concept study indicates that gluten is the trigger of symptoms in a subgroup of patients fulfilling the diagnostic criteria for NCGS. They were characterized by positive celiac genetics, lymphocytic enteritis, and clinical and histological remission after a gluten-free diet. TRIAL REGISTRATION ClinicalTrials.gov NCT02472704.
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A randomized controlled trial examining the effects of 16 weeks of moderate-to-intensive cycling and honey supplementation on lymphocyte oxidative DNA damage and cytokine changes in male road cyclists.
Hajizadeh Maleki, B, Tartibian, B, Mooren, FC, Krüger, K, FitzGerald, LZ, Chehrazi, M
Cytokine. 2016;:222-231
Abstract
The aim of this study was to investigate whether honey supplementation (70g, ninety minutes before each training session) attenuates changes in lymphocyte counts, DNA damage, cytokines, antioxidative and peroxidative biomarkers following moderate-to-intensive exercise training in male road cyclists. Healthy nonprofessional cyclists (n=24, aged 17-26years) were randomly assigned to exercise+supplement (EX+S, n=12) and exercise (EX, n=12) groups for an experimental period of 16weeks. Moderate-to-intensive exercise training increased lymphocytes DNA damage, cytokines and peroxidative biomarkers as well as decreased antioxidative biomarkers in the EX group. These changes were significantly attenuated in the EX+S group. Furthermore, for both groups the observed changes in peroxidative and antioxidative biomarkers could be correlated positively and negatively, respectively, with lymphocyte DNA damage and cytokines. Findings suggest that honey attenuates oxidative stress and lymphocyte DNA damage after exercise, activities that are most likely attributable to its high antioxidant capacity.
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Neutrophil:lymphocyte ratio is positively related to type 2 diabetes in a large-scale adult population: a Tianjin Chronic Low-Grade Systemic Inflammation and Health cohort study.
Guo, X, Zhang, S, Zhang, Q, Liu, L, Wu, H, Du, H, Shi, H, Wang, C, Xia, Y, Liu, X, et al
European journal of endocrinology. 2015;(2):217-25
Abstract
AIM: It is widely known that inflammation is related to type 2 diabetes (T2D), but few studies have shown a direct relationship between the immune system and T2D using a reliable biomarker. Neutrophil:lymphocyte ratio (NLR) is an easy-to-analyze inflammation biomarker, but few studies have assessed the relationship between NLR and T2D. In order to evaluate how NLR is related to T2D, we designed a large-scale cross-sectional and prospective cohort study in an adult population. SUBJECTS AND METHODS Participants were recruited from the Tianjin Medical University General Hospital-Health Management Centre. Both a baseline cross-sectional (n=87,686) and a prospective (n=38,074) assessment were performed. Participants without a history of T2D were followed up for ∼ 6 years (with a median follow-up of 2.7 years). Adjusted logistic and Cox proportional hazards regression models were used to assess relationships between the quintiles of NLR and T2D (covariates: age, sex, BMI, smoking status, drinking status, hypertension, hyperlipidemia, and family history of cardiovascular disease, hypertension, hyperlipidemia, or diabetes). RESULTS The prevalence and incidence of T2D were 4.9% and 6.8/1000 person-years respectively. The adjusted odds ratio and hazard ratio (95% CI) of the highest NLR quintile were 1.34 (1.21, 1.49) and 1.39 (1.09, 1.78) (both P for trend <0.01) respectively as compared to the lowest quintile of NLR. Leukocyte, neutrophil, and lymphocyte counts do not significantly predict the eventual development of T2D. CONCLUSION The present study demonstrates that NLR is related to the prevalence and incidence of T2D, and it suggests that NLR may be an efficient and accurate prognostic biomarker for T2D.
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Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection.
Cavalcante, AA, Campelo, MW, de Vasconcelos, MP, Ferreira, CM, Guimarães, SB, Garcia, JH, de Vasconcelos, PR
Nutrition (Burbank, Los Angeles County, Calif.). 2012;(4):397-402
Abstract
OBJECTIVE To evaluate the effect of enteral nutrition (EN) supplemented with l-glutamine on glycolytic parameters, inflammation, immune function, and oxidative stress in moderately ill intensive care patients with sepsis. METHODS Thirty patients received EN. Fifteen patients received EN supplemented with glutamine (30 g; GLN group) for 2 d followed by EN supplemented with calcium caseinate (30 g, CAS group), also over 2 d. The other 15 patients received EN with calcium caseinate (30 g; CAS group) for 2 d followed by EN with glutamine (30 g; GLN group), also over 2 days. One washout day with only EN was provided between every 2-d period of EN plus supplementation to all patients. Blood samples were taken before and after supplementation. RESULTS There were no changes in glycolytic parameters in either group. Leukocytes decreased in the two groups (from 13 650 to 11 500 in the CAS group, P = 0.019; from 12.850 to 11.000 in the GLN group, P = 0.046). Lymphocytes increased in the GLN group (from 954 to 1916, P < 0.0001) and were more numerous after glutamine supplementation (from 1916 to 1085, P < 0.0001, GLN versus CAS). No significant changes were observed in interleukin levels, but urea levels were higher in the GLN compared with the CAS group (50.0-47.0, P = 0.030). Glutathione plasma concentrations did not differ significantly between the groups. No significant changes were observed in the plasma glutamine and glutamate concentrations. CONCLUSIONS The EN supplemented with glutamine increased the lymphocyte count and helped to decrease lipid peroxidation but presented no effect on the antioxidant glutathione capacity and on cytokine concentrations or glycolytic parameters.
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Antioxidant effect of lemon verbena extracts in lymphocytes of university students performing aerobic training program.
Carrera-Quintanar, L, Funes, L, Viudes, E, Tur, J, Micol, V, Roche, E, Pons, A
Scandinavian journal of medicine & science in sports. 2012;(4):454-61
Abstract
Aerobic training is related to an increase in blood oxidation markers. The purpose of the present study was to investigate the antioxidant capacity of Lippia citriodora extracts (PLX(®) ) on plasma and blood cell oxidative status of university students beginning a 21 days aerobic training routine (3 days/week). Using a double-blind design, 15 male athletes (21 ± 2.1 years) were assigned to a group consuming 1.8 g/day of the plant extract (PLX(®) -group) or a placebo (PLB-group). Two blood extractions were performed at day 0 and 21, from which lymphocytes, erythrocytes and plasma were isolated. Several circulating parameters, antioxidant enzyme activities and oxidative stress markers were measured. The PLX(®) -group displayed an increased HDL-cholesterol, a modest decrease in erythrocyte number and an increased circulating urea. Activation of glutathione (GSH)-reductase was observed in erythrocytes and lymphocytes of PLX(®) -group, accompanied by lower levels of oxidative stress markers, such as malondialdehyde and protein carbonyls in plasma. The antioxidant action exerted by PLX(®) on GSH-reductase seems to be post-translational and mainly due to verbascoside, a phenylpropanoid that represents 10% (w/w) of extract content. In conclusion, PLX(®) shows antioxidant properties that could play an important role in modulating GSH-reductase activity in lymphocytes and erythrocytes and protecting plasma from exercise oxidative damage.