-
1.
Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis.
Domingues, RG, Hepworth, MR
Frontiers in immunology. 2020;:116
Abstract
Recent years have seen a revolution in our understanding of how cells of the immune system are modulated and regulated not only via complex interactions with other immune cells, but also through a range of potent inputs derived from diverse and varied biological systems. Within complex tissue environments, such as the gastrointestinal tract and lung, these systems act to orchestrate and temporally align immune responses, regulate cellular function, and ensure tissue homeostasis and protective immunity. Group 3 Innate Lymphoid Cells (ILC3s) are key sentinels of barrier tissue homeostasis and critical regulators of host-commensal mutualism-and respond rapidly to damage, inflammation and infection to restore tissue health. Recent findings place ILC3s as strategic integrators of environmental signals. As a consequence, ILC3s are ideally positioned to detect perturbations in cues derived from the environment-such as the diet and microbiota-as well as signals produced by the host nervous, endocrine and circadian systems. Together these cues act in concert to induce ILC3 effector function, and form critical sensory circuits that continually function to reinforce tissue homeostasis. In this review we will take a holistic, organismal view of ILC3 biology and explore the tissue sensory circuits that regulate ILC3 function and align ILC3 responses with changes within the intestinal environment.
-
2.
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
-
-
Free full text
-
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.
-
3.
A maintained absolute lymphocyte count predicts the overall survival benefit from eribulin therapy, including eribulin re-administration, in HER2-negative advanced breast cancer patients: a single-institutional experience.
Watanabe, J, Saito, M, Horimoto, Y, Nakamoto, S
Breast cancer research and treatment. 2020;(1):211-220
Abstract
PURPOSE Eribulin methylate (eribulin) improved the overall survival (OS) of HER2-negative advanced breast cancer (HER2-ABC) patients; however, the mechanism underlying the OS improvement has not been clarified. Several reports suggest that eribulin promotes antitumor immunity via tumor micro-environment conditioning. Recently, a maintained baseline lymphocyte count was proposed as predictive marker for eribulin therapy in HER2-ABC patients; however, no associations with the OS have been noted. We retrospectively investigated the neutrophil-to-lymphocyte ratio and absolute lymphocyte count (ALC) in HER2-ABC patients receiving eribulin and assessed the utility of eribulin re-administration for further OS improvement. METHODS HER2-ABC patients who received eribulin therapy at Shizuoka Cancer Center between November 2011 and December 2018 were retrospectively analyzed. RESULTS A total of 144 HER2-ABC (108 estrogen receptor-positive [ER+], 36 ER-) patients were identified, and 32 patients (28 ER+ , 4 ER-) were re-administered with eribulin. In the ER+ subgroup, a multivariate analysis showed that an ALC ≥ 1000/μL and re-administration were significantly associated with the OS (hazard ratio [HR] 0.503; P = 0.034 and HR 0.366; P < 0.0001, respectively), and an ALC ≥ 1000/μL was also identified as the only predictive factor for re-administration (HR 0.329; P = 0.033). In contrast, a multivariate analysis in the ER- subgroup identified no predictive markers. CONCLUSION In HER2-ER + ABC patients, ALC was identified as a predictive marker for eribulin therapy, and the re-administration of eribulin is considered a valid therapeutic option for further improvement of the OS.
-
4.
Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study.
Bolondi, G, Russo, E, Gamberini, E, Circelli, A, Meca, MCC, Brogi, E, Viola, L, Bissoni, L, Poletti, V, Agnoletti, V
World journal of emergency surgery : WJES. 2020;(1):41
Abstract
BACKGROUND Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis. METHODS We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, troponin T, lactate dehydrogenase, ferritin, serum iron, transferrin, transferrin saturation, transferrin soluble receptor, lymphocyte count and NK, CD3, CD4, CD8 and B subgroups of 31 patients during the first 2 weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with the Spearman coefficient and Mann-Whitney test. Trends over time were tested with the Kruskal-Wallis analysis. RESULTS Lymphopenia is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither ferritin nor lymphocyte count follows significant trends in ICU patients. Transferrin saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at days 3 to 6 (median 33%, IQR 26.5%, p value 0.026). The same trend is observed with serum iron levels (median 25.5 μg/L, IQR 69 μg/L at admission; median 73 μg/L, IQR 56 μg/L on days 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing haemophagocytic lymphohistiocytosis. D-dimer is elevated and progressively increases from admission (median 1319 μg/L; IQR 1285 μg/L) to days 3 to 6 (median 6820 μg/L; IQR 6619 μg/L), despite not reaching significant results. We describe trends of all the abovementioned parameters during ICU stay. CONCLUSIONS The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the intensive care unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.
-
5.
Peripheral Lymphocytes, Obesity, and Metabolic Syndrome in Young Adults: An Immunometabolism Study.
Rodríguez, CP, González, MC, Aguilar-Salinas, CA, Nájera-Medina, O
Metabolic syndrome and related disorders. 2018;(7):342-349
Abstract
BACKGROUND Obesity is characterized by a low-intensity chronic inflammatory process in which immune system cells interact in a complex network, which affects systemic metabolic processes. This raises interest in analyzing possible changes in the proportions of immune system cells in individuals with obesity with and without metabolic syndrome (MS), in relation to their body composition. METHODS Circulating cells were analyzed with flow cytometry in young adults: monocytes, granulocytes, lymphocytes (T, B, and natural killer [NK]), TCD4+CD62-, TCD8+CD28-, and naive and memory cells of TCD3+ and TCD4+. Body composition was obtained by bioelectrical impedance analysis and dual-energy X-ray absorptiometry, and metabolic parameters. RESULTS A total of 169 persons were evaluated: 20% presented normal body mass index (BMI); 49% was overweight, and 31% had obesity; 28% had MS. It was observed that with an increase in BMI and visceral adipose tissue increase (VATI), body composition and biochemical variables were negatively altered. With regard to cell subpopulations, total lymphocytes increased and granulocytes and NK lymphocytes decreased in patients with MS and VATI. Memory cells increased with BMI and VATI. In individuals with MS, monocytes, and NK lymphocytes comprised a negative association with VAT, fat mass, and skeletal muscle mass (SMM). In individuals with MS and VATI, a negative correlation was observed between monocytes and SMM. CONCLUSIONS Significant changes were detected in the subpopulations of lymphocytes, suggesting that weight gain, SMM, and VAT accumulation gave rise to immunological changes at the peripheral level, and the presence of increased memory cells could be related to low-intensity chronic inflammation.
-
6.
The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.
Lange, A, Jaskula, E, Lange, J, Dworacki, G, Nowak, D, Simiczyjew, A, Mordak-Domagala, M, Sedzimirska, M
PloS one. 2018;(1):e0190525
Abstract
We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.
-
7.
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.
-
8.
Desensitization to chemical and food sensitivities by low-dose immunotherapy ascertained by provocation neutralization is associated with reduced influx of calcium ions into lymphocytes.
Puri, BK, Howard, JM, Monro, JA
Journal of complementary & integrative medicine. 2017;(2)
-
-
Free full text
-
Abstract
Background Food and chemical sensitivities have detrimental effects on health and the quality of life. The natural course of such sensitivities can potentially be altered through various types of allergen-specific immunotherapy, including low-dose immunotherapy. The molecular mechanism by which low-dose immunotherapy causes desensitization has not thus far been elucidated. While resting lymphocytes maintain a low cytosolic calcium ion concentration, antigen receptor signaling results in calcium ion influx, predominantly via store-operated calcium channels. We therefore hypothesized that desensitization by low-dose immunotherapy is associated with reduced influx of calcium ions into lymphocytes. The aim of this study was to test this hypothesis. Methods Intracellular lymphocytic calcium ion concentrations were assayed in a total of 47 patients, following incubation with picogram amounts of the test allergens, using a cell-permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy. Results Low-dose immunotherapy was associated with a reduction in lymphocytic intracellular calcium ion concentration following treatment of: 23 % for metabisulfite sensitivity (p<0.0004); 12 % for salicylate sensitivity (p<0.01); 23 % for benzoate sensitivity (p<0.01); 30 % for formaldehyde sensitivity (p<0.0001); 16 % for sensitivity to petrol exhaust (p<0.003); 16 % for natural gas sensitivity (p<0.001); 13 % for nickel sensitivity (p<0.05); 30 % for sensitivity to organophosphates (p<0.01); and 24 % for sensitivity to nitrosamines (p<0.05). Conclusions Low-dose immunotherapy may affect baseline levels of intracellular calcium in lymphocytes, supporting the premise that allergens affect cell signaling in immune cells and provocation neutralization immunotherapy helps to promote more normal immune cell signaling.