A Fragrant Environment Containing α-Pinene Suppresses Tumor Growth in Mice by Modulating the Hypothalamus/Sympathetic Nerve/Leptin Axis and Immune System

The environment is thought to affect outcomes in patients with cancer; however, this relationship has not been proven directly. Recently, an enriched environment, as a model of a positive environment, has been shown to suppress tumor growth by lowering leptin production through a pathway involving the hypothalamus/sympathetic nerve/leptin axis. We previously reported that a fragrant environment (FE) containing α-pinene suppressed tumor growth in mice; however, the underlying mechanism has not been elucidated. Accordingly, in this study, we investigated changes in the neuroendocrine and immune systems following exposure to an FE. Mice were exposed to α-pinene (5 h/day) for 4 weeks prior to tumor implantation with murine melanoma cells and 3 weeks after transplantation. In addition to the evaluation of tumor growth, the blood, spleen, and hypothalamus were collected 3 weeks after transplantation, and neuroendocrinological and immunological parameters were measured. Tumor size was ~40% smaller in mice exposed to FE. Moreover, plasma noradrenaline concentrations, which reflected sympathetic nervous activity, tended to increase, and leptin levels were significantly decreased in FE-exposed mice. Levels of stress hormones, such as plasma corticosterone and adrenaline, did not change in the 2 groups. In the hypothalamus, brain-derived neurotrophic factor protein levels and glucose-1-phosphate concentrations were decreased in the FE group. Additionally, numbers of B cells, CD4+ T cells, CD8+ T cells, and natural killer cells increased in the FE-exposed mice. These neurohormonal and immunological changes in the FE-exposed mice suggested that the FE may activate the hypothalamus/sympathetic nerve/leptin axis and immune system, thereby retarding tumor growth.

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Non-linear tumor-immune interactions arising from spatial metabolic heterogeneity

10.1101/038273 ◽

2016 ◽

Cited By ~ 4

Author(s):

Mark Robertson-Tessi ◽

Robert J. Gillies ◽

Robert A. Gatenby ◽

Alexander R. A. Anderson

Keyword(s):

Mathematical Model ◽

T Cells ◽

Immune System ◽

Tumor Growth ◽

Cytotoxic T Cells ◽

Non Linear ◽

Metabolic Heterogeneity ◽

Multiscale Mathematical Model ◽

Tumor Phenotypes

AbstractA hybrid multiscale mathematical model of tumor growth is used to investigate how tumoral and microenvironmental heterogeneity affect the response of the immune system. The model includes vascular dynamics and evolution of metabolic tumor phenotypes. Cytotoxic T cells are simulated, and their effect on tumor growth is shown to be dependent on the structure of the microenvironment and the distribution of tumor phenotypes. Importantly, no single immune strategy is best at all stages of tumor growth.

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Exosome-delivered miR-15a/16 Targets PD-L1 to Inhibit Immune Escape in Gastric Cancer

10.21203/rs.3.rs-1082480/v1 ◽

2021 ◽

Author(s):

Changliang Yang ◽

Qiumo Zhang ◽

Mengsi Zuo ◽

Jiayu Yang ◽

Tao Ning ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Tumor Growth ◽

Crucial Role ◽

Immune Escape ◽

Underlying Mechanism ◽

Immune Checkpoints

Abstract Recently, immunotherapy targeting immune checkpoints, especially PD-1/PD-L1 blockade, has been demonstrated to play a crucial role in numerous malignancies to rejuvenate disabled T cells to achieve long-term remission. However, the underlying mechanism of PD-L1 expression dysregulation in gastric cancer (GC) has not been revealed. The present study aimed to determine whether artificially modified exosomes transporting miR-15a/16 target PD-L1 and inhibit immune escape in GC. Modified exosomes serve as novel nanoliposomes to suppress tumor growth and inhibit immune escape by targeting PD-L1 in vivo and in vitro. The present study also suggested that the combination of exosomal miR-15a/16 can be used in immunotherapy against tumors, including gastric cancer.

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Consequences of the Lack of CD73 and Prostatic Acid Phosphatase in the Lymphoid Organs

Mediators of Inflammation ◽

10.1155/2014/485743 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Gennady G. Yegutkin ◽

Kaisa Auvinen ◽

Marika Karikoski ◽

Pia Rantakari ◽

Heidi Gerke ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Acid Phosphatase ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Ex Vivo ◽

Prostatic Acid Phosphatase ◽

Potential Contribution ◽

Double Knockout ◽

Immunological Parameters

CD73, ecto-5′-nucleotidase, is the key enzyme catalyzing the conversion of extracellular AMP to adenosine that controls vascular permeability and immunosuppression. Also prostatic acid phosphatase (PAP) possesses ecto-5′-nucleotidase/AMPase activity and is present in leukocytes. However, its role related to immune system is unknown. Therefore, we analyzed enzymatic activities and leukocyte subtypes of CD73 and PAP knockouts and generated CD73/PAP double knockout mice to elucidate the contribution of CD73 and PAP to immunological parameters. Enzymatic assays confirmed the ability of recombinant human PAP to hydrolyze [3H]AMP, although at much lower rate than human CD73. Nevertheless, 5′-nucleotidase/AMPase activity in splenocytes and lymphocytes from PAP−/−mice tended to be lower than in wild-type controls, suggesting potential contribution of PAP, along with CD73, into lymphoid AMP metabolism ex vivo. Single knockouts had decreased number ofCD4+/CD25+/FoxP3+regulatory T cells in thymus and CD73/PAP double knockouts exhibited reduced percentages of CD4+cells in spleen, regulatory T cells in lymph nodes and thymus, and CD4+and CD8+cells in blood. These findings suggest that PAP has a synergistic role together with CD73 in the immune system by contributing to the balance of leukocyte subpopulations and especially to the number of regulatory T cells in lymph nodes and thymus.

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Investigation of Murine T-Cells and Cancer Cells under Thermal Stressors and 2D Slow Rotating System Effects as a Testbed for Suborbital Flights

Gravitational and Space Research ◽

10.2478/gsr-2019-0006 ◽

2019 ◽

Vol 7 (1) ◽

pp. 45-61

Author(s):

Pedro J. Llanos ◽

Kristina Andrijauskaite

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Cancer Cells ◽

T Cell Activation ◽

Cell Activation ◽

Feasibility Studies ◽

Immunological Parameters ◽

Suborbital Flights ◽

Suborbital Flight

AbstractResearch indicates that exposure to microgravity leads to immune system dysregulation. However, there is a lack of clear evidence on the specific reasons and precise mechanisms accounting for these immune system changes. Past studies investigating space travel-induced alterations in immunological parameters report many conflicting results, explained by the role of certain confounders, such as cosmic radiation, individual body environment, or differences in experimental design. To minimize the variability in results and to eliminate some technical challenges, we advocate conducting thorough feasibility studies prior to actual suborbital or orbital space experiments. We show how exposure to suborbital flight stressors and the use of a two-dimensional slow rotating device affect T-cells and cancer cells survivability. To enhance T-cell activation and viability, we primed them alone or in combination with IL-2 and IL-12 cytokines. Viability of T-cells was assessed before, during the experiment, and at the end of the experiment for which T-cells were counted every day for the last 4 days to allow the cells to form clear structures and do not disturb their evolution into various geometries. The slow rotating device could be considered a good system to perform T-cell activation studies and develop cell aggregates for various types of cells that react differently to thermal stressors.

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Elevated levels and Clinical Association of Serum Cytokines in Untreated HIV-1 Infection

10.21203/rs.3.rs-534115/v1 ◽

2021 ◽

Author(s):

Na Zhang ◽

Chang-Xin Yan ◽

Shuang-Mei Yu ◽

Xiao-Xiong Wang ◽

Lei Teng ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Hiv Infection ◽

Early Stage ◽

Serum Levels ◽

Underlying Mechanism ◽

Cell Counts ◽

Aids Progression ◽

Hiv 1

Abstract Background Human immunodeficiency virus type 1 (HIV-1) infection disturbs the balance of CD4+ T cells and monocytes in the immune system. In the early stage of infection, the virus stimulates the activation and proliferation of immune cells, induces the release of cytokines, destroys CD4+ T cells, and accelerates HIV-1 replication and AIDS progression. It is essential to explore cytokine changes after HIV-1 infection and further understand the underlying mechanism of HIV infection. Methods In this study, we enrolled 38 HIV-infected subjects and 30 healthy subjects. We measured and compared CD4+ T cell counts and the serum cytokine levels in different groups. Results Our results showed significantly higher serum levels of IL-1β, IL-2, IL-4, IL-7, IL-10, IL-17, IFN-γ, and TNF-α in HIV-infected patients. Higher levels of IL-6 and IL-17 were observed in the < 200/mL CD4+ T cell count group, and higher levels of IL-2 were observed in the CCR5-tropic HIV strain group. Conclusion In conclusion, we found that HIV infection-induced activation of the immune system and cytokines could predict the severity of HIV disease and regulate HIV infection and replication differently depending on the type of virus strain.

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Adaptive discrimination of antigen risk by predictive coding in immune system

10.1101/2021.12.12.472285 ◽

2021 ◽

Author(s):

Kana Yoshido ◽

Naoki Honda

Keyword(s):

Machine Learning ◽

Immune Response ◽

T Cells ◽

Immune System ◽

Prediction Error ◽

Memory T Cells ◽

Predictive Coding ◽

Underlying Mechanism ◽

Learning System ◽

Past Experiences

The immune system discriminates between harmful and harmless antigens based on past experiences; however, the underlying mechanism is largely unknown. From the viewpoint of machine learning, the learning system predicts the observation and updates the prediction based on prediction error, a process known as predictive coding. Here, we modeled the population dynamics of T cells by adopting the concept of predictive coding; helper and regulatory T cells predict the antigen amount and excessive immune response, respectively. Their prediction error signals, possibly via cytokines, induce their differentiation to memory T cells. Through numerical simulations, we found that the immune system identifies antigen risks depending on the concentration and input rapidness of the antigen. Further, our model reproduced history-dependent discrimination, as in allergy onset and subsequent therapy. Together, this study provided a novel framework to improve our understanding of how the immune system adaptively learns the risks of diverse antigens.

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Regional Sympathetic Nervous Activation after a Large Meal in Humans

Clinical Science ◽

10.1042/cs0890145 ◽

1995 ◽

Vol 89 (2) ◽

pp. 145-154 ◽

Cited By ~ 62

Author(s):

Helen S. Cox ◽

David M. Kaye ◽

Jane M. Thompson ◽

Andrea G. Turner ◽

Garry L. Jennings ◽

...

Keyword(s):

Skeletal Muscle ◽

Oxygen Consumption ◽

Sympathetic Nerve ◽

Muscle Sympathetic Nerve Activity ◽

Nervous Activity ◽

High Energy ◽

Whole Body ◽

Sympathetic Nervous Activity ◽

Sympathetic Nervous ◽

Large Meal

1. To investigate the link between post-prandial thermogenesis and sympathetic nervous activation we have studied the effects of a single large meal on regional sympathetic nervous activity in healthy, lean subjects. 2. In nine male subjects, noradrenaline spillover was measured from the heart, kidney and liver using isotope dilution, both while fasting and after consumption of a high-energy liquid meal of composition 53% carbohydrate, 32% fat and 15% protein (energy value 2.64–3.51 MJ). Regional oxygen consumption, whole-body oxygen consumption and, in a subset of subjects, muscle sympathetic nerve firing (microneurography) were also measured. 3. Both whole-body oxygen consumption (P < 0.03) and total body spillover of noradrenaline (P < 0.01) rose after the meal, with peak increases of 24% and 56% respectively. Spillover of noradrenaline from the heart was unchanged, that from the hepatosplanchnic circulation increased marginally (0.377 nmol/min to 0.480 nmol/min, P = 0.09), while renal noradrenaline spillover more than doubled (0.440 nmol/min to 0.937 nmol/min, P < 0.05). Skeletal muscle sympathetic nerve activity (peroneal nerve) increased from 7.7 bursts/min at rest to peak at 17.9 bursts/min 60 min after the meal in the three subjects in whom stable recordings were obtained. 4. The meal increased oxygen consumption in the kidneys and liver significantly, from 11.5 ± 1.6 ml/min to 14.5 ± 1.1 ml/min and from 46 ± 7 ml/min to 57 ± 6 ml/min respectively (P < 0.05), but not in the heart. 5. Consumption of a large meal produces a substantial and relatively selective increase in sympathetic outflow to the kidneys and skeletal muscle. While resting regional oxygen consumptions and noradrenaline spillovers were related, the changes that occurred in each were unrelated, so that no direct relationship could be demonstrated between post-prandial thermogenesis and sympathetic activity.

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Selegiline improves cardiac sympathetic terminal function and β-adrenergic responsiveness in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h1283 ◽

2000 ◽

Vol 279 (3) ◽

pp. H1283-H1290 ◽

Cited By ~ 6

Author(s):

Junya Shite ◽

Erdon Dong ◽

Hiroya Kawai ◽

Suzanne Y. Stevens ◽

Chang-Seng Liang

Keyword(s):

Heart Failure ◽

Sympathetic Nerve ◽

Baroreflex Sensitivity ◽

Neuroprotective Effect ◽

Nervous Activity ◽

Left Ventricular ◽

Sympathetic Nervous Activity ◽

Plasma Norepinephrine ◽

Uptake Activity ◽

Fractional Shortening

Selegiline is a centrally acting sympatholytic agent with neuroprotective properties. It also has been shown to promote sympathetic reinnervation after sympathectomy. These actions of selegiline may be beneficial in heart failure that is characterized by increased sympathetic nervous activity and functional sympathetic denervation. Twenty-seven rabbits with rapid cardiac pacing (360 beats/min, 8 wk) and twenty-three rabbits without pacing were randomly assigned to receive selegiline (1 mg/day, 8 wk) or placebo. Rapid pacing increased plasma norepinephrine (NE) and decreased left ventricular fractional shortening, baroreflex sensitivity, cardiac sympathetic nerve terminal profiles, cardiac NE uptake activity, and myocardial β-adrenoceptor density. Selegiline administration to animals with rapid ventricular pacing attenuated the increase in plasma NE and decreases in fractional shortening, baroreflex sensitivity, sympathetic nerve profiles, NE uptake activity and β-adrenoceptor density. Thus selegiline appears to exert a sympatholytic and cardiac neuroprotective effect in pacing-induced cardiomyopathy. The effects are potentially beneficial because selegiline not only improves cardiac function but also increases baroreflex sensitivity in heart failure.

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Abstract P304: A Sympathetic-cholinergic Pathway Performs a Connection Between Brain and Spleen, to Prime Immune System and Induce Arterial Hypertension

Hypertension ◽

10.1161/hyp.68.suppl_1.p304 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Daniela Carnevale ◽

Marialuisa Perrotta ◽

Fabio Pallante ◽

Lorenzo Carnevale ◽

Giuseppe Cifelli ◽

...

Keyword(s):

Immune System ◽

Nervous Activity ◽

Firing Frequency ◽

Sympathetic Nervous Activity ◽

Immune System Activation ◽

Cholinergic Pathway ◽

Sympathetic Nervous ◽

The Brain ◽

Sympathetic Pathway

It is now widely recognized that immune system has a crucial role in hypertension. Various studies have demonstrated that the activation of adaptive immunity, and in particular of T cells, is a crucial moment in the onset and maintaining of hypertension induced by various stimuli in mice. Our previous studies have shown that hypertensive stimuli couple the sympathetic nervous system to determine the activation of splenic immune system. However, how the brain-to-spleen connection is realized in hypertension remains unknown. In this study we demonstrate that mice subjected to various hypertensive stimuli (AngII, DOCA-salt) show an increase of sympathetic nervous activity recorded in vivo in the splenic nerve (Firing Frequency: AngII 131±17 vs Veh 30±10 spikes/10 min, p<0.001). We also show how the sympathetic pathway induced by pro-hypertensive stimuli has its origin in the brain, converging into the spleen through a cholinergic-sympathetic connection that is realized through the vagus-splenic nerve drive and mediated at the molecular level by cholinergic nicotinic receptors at the level of celiac ganglion. In fact, we show that in celiac vagotomized mice, i.e. mice subjected to a procedure inhibiting vagal efferents but not central afferents, the splenic nervous drive induced by AngII was absent (AngII+VagX 21±4 vs AngII+sham 148±29 spikes/10 min, p<0.001). The same result was shown in α7 cholinergic nicotinic receptor KO mice, a receptor typically expressed by neurons in the peripheral ganglia (α7nAChR KO AngII 43±8 vs WT AngII 141±27 spikes/10 min, p<0.01). Moreover, we found that this cholinergic-sympathetic pathway was necessary to allow the activation of T cell costimulation and egression upon hypertensive challenges. Our results highlight a cholinergic-sympathetic pathway played by vagus-splenic nerves and responsible for immune system activation in response to hypertensive stimuli. We believe our results are significant because they reveal a previously unknown sympathetic pathway in hypertension for the first time. The brain-to-spleen connection realized through a cholinergic-sympathetic nervous drive that resembles the cholinergic anti-inflammatory pathway identified by immunologists in endotoxemia.

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A novel combination of chemotherapy and immunotherapy controls tumor growth in mice with a human immune system

10.1101/191031 ◽

2017 ◽

Author(s):

Aude Burlion ◽

Rodrigo N. Ramos ◽

KC Pukar ◽

Kélhia Sendeyo ◽

Aurélien Corneau ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Dendritic Cells ◽

Immune System ◽

Regulatory T Cells ◽

Tumor Growth ◽

Humanized Mice ◽

Tumor Control ◽

Human Immune System ◽

Human Immune

AbstractMice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.γc-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4+ and CD8+ T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS+ CD4+ regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4+ T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. However, depletion of human CD8+ T cells only marginally affected tumor control whereas depletion of murine myeloid cells abrogated the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice and highlight the crucial implication of innate immunity in treatment efficacy, opening new perspectives for the treatment of breast cancer.One sentence summaryICOS expressed on Tregs is a promising target to improve tumor immunity in humansAbbreviationsICOSInducible CostimulatoryNSGNOD.SCID.gc-nullTregregulatory T cellsCTXcyclophosphamideHuMicehumanized miceCyTOFcytometry time-of-flighttSNEtdistributed stochastic neighbor embeddingpDCsplasmacytoid dendritic cellsDCdendritic cellsICDimmunogenic cell death

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