Supplementation with antioxidant micronutrients in pregnant women with obesity: a randomized controlled trial.

BACKGROUND/OBJECTIVE: Obesity increases maternal morbidity and adversely affects child health. Maternal inflammation may play a role in adverse outcomes. The objective of this study was to determine whether providing a higher dose of antioxidant micronutrients to pregnant women with obesity would raise concentrations of key antioxidant vitamins and impact inflammation and oxidative stress during pregnancy. SUBJECTS/METHODS: This was a double-blind, randomized controlled trial. We recruited pregnant women with a body mass index (BMI) ≥ 30 kg/m2 at their initial prenatal visit ( < 13 weeks gestation) and collected blood and urine samples at baseline, 24-28 weeks, and 32-36 weeks to measure micronutrient concentrations (vitamin C, E, B6 and folate), markers of inflammation (C-reactive protein, interleukin-6, 8, and 1ß) and oxidative stress (8-epi-PGF2α and malondialdehyde). We collected maternal and infant health data from enrollment to delivery as secondary outcomes. We enrolled 128 participants (64 in each arm), and 98 (49 in each arm) completed follow-up through delivery. INTERVENTION: Both groups received a standard prenatal vitamin containing the recommended daily allowance of micronutrients in pregnancy. In addition, the intervention group received a supplement with 90 mg vitamin C, 30 αTU vitamin E, 18 mg vitamin B6, and 800 µg folic acid, and the control group received a placebo. RESULTS: The intervention group had higher vit B6 (log transformed (ln), ß 24-28 weeks: 0.76 nmol/L (95% CI: 0.40, 1.12); ß 32-36 weeks: 0.52 nmol/L (95% CI: 0.17, 0.88)) than the control group. Vitamins C, E, erythrocyte RBC folate concentrations did not differ by randomization group. The intervention did not impact biomarkers of inflammation or oxidative stress. There were no differences in maternal or neonatal clinical outcomes by randomization group. CONCLUSIONS: Higher concentrations of antioxidant vitamins during pregnancy increased specific micronutrients and did not impact maternal inflammation and oxidative stress, which may be related to dosing or type of supplementation provided. CLINICAL TRIAL REGISTRATION: Clinical Trial Identification Number: NCT02802566; URL of the Registration Site: www. CLINICALTRIALS: gov .

Increased fruit and vegetable consumption prevents dysregulated immune and inflammatory responses in high-fat diet-induced obese mice.

BACKGROUND: Obesity is often associated with impaired immune responses, including enlarged spleen, increased inflammation, and impaired T cell-mediated function, which may lead to increased susceptibility to infections. Bioactive compounds found in various fruits and vegetables (F&V) have been shown to have strong anti-inflammatory effects. However, few prospective studies have examined the effects of F&V on preventing obesity-associated dysregulation of immune and inflammatory responses. OBJECTIVE: To determine the impact of different levels of a mixture of F&V incorporated in a high-fat diet (HFD) on immune function changes in a diet-induced obesity animal model. METHODS: Six-week-old male C57BL/6J mice were randomly assigned to one of five groups (n = 12/group): matched low-fat control (LF, 10% kcal fat) or high-fat diet (HFD, 45% kcal fat) supplemented with 0%, 5%, 10%, or 15% (wt/wt) freeze-dried powder of the most consumed F&V (human equivalent of 0, 3, 5-7, 8-9 servings/d, respectively) for 20 weeks. Spleen weight was recorded, and the immunophenotype of splenocytes was evaluated by flow cytometry. Ex vivo splenic lymphocyte proliferation was assessed by thymidine incorporation and serum cytokines were measured by Meso Scale Discovery. RESULTS: Mice fed the HFD had significantly higher spleen weight, decreased splenic CD8+ lymphocytes, suppressed T lymphocyte proliferation, and reduced serum IL-1ß and IFN-γ levels compared to those fed the LF diet. Feeding mice with the HFD supplemented with 10% or 15% F&V restored HFD-associated changes of these affected biomarkers compared to those fed HFD only. Further, a significant correlation was found between immunological markers and F&V level. CONCLUSIONS: These results suggest that increased consumption of F&V has beneficial effects in preventing HFD-associated dysregulation of immune function.

Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging.

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity upon Viral Infection and Advanced Age.

Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx (NP) but can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human coinfection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2-month-old) mice, coinfection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease, and mortality in a fraction of mice. In aged mice (18 to 24 months), coinfection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted alpha interferon (IFN-α) production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden, likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and coinfection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.

Dietary Fruit and Vegetable Supplementation Suppresses Diet-Induced Atherosclerosis in LDL Receptor Knockout Mice.

BACKGROUND: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood. OBJECTIVES: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined. METHODS: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed. RESULTS: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis. CONCLUSIONS: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation.

A Novel Combination of Fruits and Vegetables Prevents Diet-Induced Hepatic Steatosis and Metabolic Dysfunction in Mice.

BACKGROUND: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. OBJECTIVES: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. METHODS: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. RESULTS: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. CONCLUSIONS: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.

Regulatory role of vitamin E in the immune system and inflammation.

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused on α-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application. © 2018 IUBMB Life, 71(4):487-494, 2019.

Dietary supplementation with blueberry partially restores T-cell-mediated function in high-fat-diet-induced obese mice.

Blueberry, rich in antioxidant and anti-inflammatory phytochemicals, has been demonstrated to lower inflammatory status in adipose induced by high-fat diet (HFD) and obesity. The effect of blueberry on systemic immune functions has not been examined. C57BL/6 mice were randomised to one of three diets - low-fat diet (LFD), HFD and HFD plus 4 % (w/w) blueberry (HFD+B) - for 8 or 12 weeks. Ex vivo T-cell mitogens (concanavalin A (Con A); phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 weeks, both HFD groups weighed more (>4 g) than the LFD group; after 12 weeks, HFD+B-fed mice weighed more (>6 g) and had 41 % more adipose tissue than HFD-fed mice (P<0·05). After 12 weeks, T-cell proliferation was less in both HFD groups, compared with the LFD group. HFD-associated decrements in T-cell proliferation were partially (10-50 %) prevented by blueberry supplementation. At 12 weeks, splenocytes from HFD mice, but not from HFD+B mice, produced 51 % less IL-4 (CD3/CD28) and 57 % less interferon-γ (Con A) compared with splenocytes from LFD mice (P<0·05). In response to lipopolysaccharide challenge, splenocytes from both HFD groups produced 24-30 % less IL-6 and 27-33 % less TNF-α compared with splenocytes from LFD mice (P<0·05), indicating impaired acute innate immune response. By demonstrating deleterious impacts of HFD feeding on T-cell proliferation and splenocyte immune responses, our results provide insights into how HFD/obesity can disrupt systemic immune function. The protective effects of blueberry suggest that dietary blueberry can buttress T-cell and systemic immune function against HFD-obesity-associated insults.

Consensus Statement Immunonutrition and Exercise.

In this consensus statement on immunonutrition and exercise, a panel of knowledgeable contributors from across the globe provides a consensus of updated science, including the background, the aspects for which a consensus actually exists, the controversies and, when possible, suggested directions for future research.

The α-tocopherol form of vitamin E reverses age-associated susceptibility to streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment.

Streptococcus pneumoniae infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the α-tocopherol (α-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil responses as a preventive strategy to mitigate the age-associated decline in resistance to S. pneumoniae, young (4 mo) and old (22-24 mo) C57BL/6 mice were fed a diet containing 30-PPM (control) or 500-PPM (supplemented) α-Toc for 4 wk and intratracheally infected with S. pneumoniae. Aged mice fed a control diet were exquisitely more susceptible to S. pneumoniae than young mice. At 2 d postinfection, aged mice suffered 1000-fold higher pulmonary bacterial burden, 2.2-fold higher levels of neutrophil recruitment to the lung, and a 2.25-fold higher rate of lethal septicemia. Strikingly, α-Toc supplementation of aged mice resulted in a 1000-fold lower bacterial lung burden and full control of infection. This α-Toc-induced resistance to pneumococcal challenge was associated with a 2-fold fewer pulmonary neutrophils, a level comparable to S. pneumoniae-challenged, conventionally fed young mice. α-Toc directly inhibited neutrophil egress across epithelial cell monolayers in vitro in response to pneumococci or hepoxilin-A3, an eicosanoid required for pneumococcus-elicited neutrophil trans-epithelial migration. α-Toc altered expression of multiple epithelial and neutrophil adhesion molecules involved in migration, including CD55, CD47, CD18/CD11b, and ICAM-1. These findings suggest that α-Toc enhances resistance of aged mice to bacterial pneumonia by modulating the innate immune response, a finding that has potential clinical significance in combating infection in aged individuals through nutritional intervention.

The rise, the fall and the renaissance of vitamin E.

This review deals with the expectations of vitamin E ability of preventing or curing, as a potent antioxidant, alleged oxidative stress based ailments including cardiovascular disease, cancer, neurodegenerative diseases, cataracts, macular degeneration and more. The results obtained with clinical intervention studies have highly restricted the range of effectiveness of this vitamin. At the same time, new non-antioxidant mechanisms have been proposed. The new functions of vitamin E have been shown to affect cell signal transduction and gene expression, both in vitro and in vivo. Phosphorylation of vitamin E, which takes place in vivo, results in a molecule provided with functions that are in part stronger and in part different from those of the non-phosphorylate compound. The in vivo documented functions of vitamin E preventing the vitamin E deficiency ataxia (AVED), slowing down the progression of non-alcoholic steato-hepatitis (NASH), decreasing inflammation and potentiating the immune response are apparently based on these new molecular mechanisms. It should be stressed however that vitamin E, when present at higher concentrations in the body, should exert antioxidant properties to the extent that its chromanol ring is unprotected or un-esterified.

Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE).

An increasing recognition has emerged of the complexities of the global health agenda­specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations.

Dietary supplementation with white button mushrooms augments the protective immune response to Salmonella vaccine in mice.

We previously showed that dietary white button mushrooms (WBMs) enhanced natural killer cell activity and that in vitro WBM supplementation promotes maturation and function of dendritic cells (DCs). The current study investigated whether WBM consumption would enhance pathogen-specific immune response using a Salmonella vaccination and infection animal model. C57BL/6 mice were fed diets containing 0%, 2%, or 5% WBM for 4 wk before oral vaccination with live attenuated Salmonella typhimurium SL1479. Four weeks after immunization, mice were orally infected with virulent Salmonella typhimurium SL1344. Immunization increased animal survival and, among immunized mice, the 2% WBM group had a higher survival rate than the other groups. Next, we fed mice 2% WBMs to determine the immunological mechanism underlying the WBM-potentiated protective effect. We found that WBM supplementation increased Salmonella-specific blood immunoglobulin (Ig) G and fecal IgA concentrations. WBM-fed mice also had a higher IgG2a and unchanged IgG1 production, leading to an elevated IgG2a:IgG1 ratio and indicating an enhanced T helper 1 response. Consistent with these results, WBM-fed mice had higher interferon-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-17A production and unchanged IL-4 production in their splenocytes after polyclonal (anti-CD3/CD28) or antigen-specific stimulation. Furthermore, WBM-fed mice had more DCs in the spleen, and these DCs expressed higher levels of activation markers CD40 and major histocompatibility complex-II. These mice also produced more IL-12 and TNF-α postimmunization. Together, these results suggest that WBMs may improve Salmonella vaccine efficacy through an enhanced adaptive immune response.

Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function.

Study protocol for a zinc intervention in the elderly for prevention of pneumonia, a randomized, placebo-controlled, double-blind clinical pilot trial.

Pneumonia is a major public health problem for older adults, being one of the leading causes of hospitalization and death, particularly for elderly nursing home residents. We previously conducted a clinical trial in which we demonstrated that 29% of nursing home residents had low serum zinc levels coinciding with a two-fold increase in pneumonia incidence and duration in comparison to individuals with adequate serum zinc levels. However, causality could not be inferred and necessitates a double-blind clinical trial. To determine the appropriate supplementation dose for such a trial we are conducting a randomized, placebo-controlled, double-blind clinical pilot trial aimed at delineating the optimal dosage (30 and 60 mg/day elemental Zn) and establishing safety. The results from the pilot study will be leveraged to inform our larger randomized clinical trial designed to study the effect of zinc supplementation in nursing home elderly with low serum zinc levels on respiratory infections, antibiotic use, and duration of sick days with pneumonia. In tandem with dose optimization, we will evaluate the correlation between serum zinc and pan-T cell zinc levels, given that T cells and their zinc levels are important in the response and resolution of respiratory infections but whose correlation has only been extrapolated and not demonstrated. Herein we present the study rationale and protocol, as well as discuss specific challenges we encountered in securing a manufacturer for the study agents and when recruiting from nursing home populations during the COVID-19 pandemic. In light of these experiences, we provide recommendations for future clinical trials under circumstances where supply chains are disrupted, and recruitment pools are constrained or unavailable. Clinical trial registration: https://clinicaltrials.gov/, NCT05527899.

Corrigendum: Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

[This corrects the article DOI: 10.3389/fnut.2023.1230061.].

Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets.

The green tea component epigallocatechin-3-gallate (EGCG) may be beneficial in autoimmune diseases; however, the underlying mechanisms are not well understood. In this study, we determined the effect of EGCG on the development of experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis, and the underlying mechanisms. Female C57BL/6 mice were fed EGCG (0%, 0.15%, 0.3%, and 0.6% in diet) for 30 days and then immunized with specific antigen myelin oligodendrocyte glycoprotein 35-55. EGCG dose dependently attenuated clinical symptoms and pathological features (leukocyte infiltration and demyelination) in the central nervous system and inhibited antigen-specific T-cell proliferation and delayed-type hypersensitivity skin response. We further showed that EGCG reduced production of interferon-γ, IL-17, IL-6, IL-1ß, and tumor necrosis factor-α; decreased types 1 and 17 helper T cells (Th1 and Th17, respectively); and increased regulatory T-cell populations in lymph nodes, the spleen, and the central nervous system. Moreover, EGCG inhibited expression of transcription factors T-box expressed in T cells and retinoid-related orphan receptor-γt, the specific transcription factor for Th1 and Th17 differentiation, respectively; the plasma levels of intercellular adhesion molecule 1; and CCR6 expression in CD4(+) T cells. These results indicate that EGCG may attenuate experimental autoimmune encephalomyelitis autoimmune response by inhibiting immune cell infiltration and modulating the balance among pro- and anti-autoimmune CD4(+) T-cell subsets. Thus, we identified a novel mechanism that underlies EGCG's beneficial effect in autoimmune disease.

In vivo regulation of gene transcription by alpha- and gamma-tocopherol in murine T lymphocytes.

Of the 8 different analogues (α-, ß-, γ-, δ-tocopherols and tocotrienols) designated as vitamin E, alpha-tocopherol (α-T) has been mostly studied, together with gamma-tocopherol (γ-T) which is abundant in the US diet. We compared the effect of dietary supplementation with adequate or high doses of α-T or γ-T on the number and type of genes expressed following T cell activation. C57BL/6 mice were fed diets containing adequate (30 ppm) or high (500 ppm) amounts of α-T or γ-T for 4 weeks. Spleen T cells were stimulated ex vivo with plate-bound anti-CD3 and soluble anti-CD28, and gene expression changes were assessed by gene array analysis. The data obtained indicated significant qualitative and quantitative differences between the two analogs in regulating gene expression induced by T cell stimulation. Genes were found uniquely responding to either high α-T (e.g. induced: CD40 ligand, lymphotoxin A) or γ-T (e.g. repressed: poliovirus receptor-related-2). Interestingly, in stimulated T-cells from mice supplemented with high amounts of α-T a bigger number of genes were activated than in mice supplemented with the same amounts of γ-T; under the same conditions γ-T repressed the expression of a number of genes larger than α-T. It is possible that the observed diminution in gene expression in T cells after high γ-T in vivo supplementation modulates inflammation or other T cell mediated functions.

Obesity impairs cell-mediated immunity during the second trimester of pregnancy.

OBJECTIVE: Obese pregnancy is associated with significantly higher rates of infection, which can harm both mother and fetus. The objective of this study was to determine the impact of obesity on maternal blood immune function. STUDY DESIGN: This was a cross-sectional, case control study of 15 obese (Ob) and 15 lean (Lc) subjects. Immune cell subsets, intracellular and serum cytokine production, and lymphocyte proliferation were measured in maternal blood during the second trimester of pregnancy. RESULTS: Obese women had a significantly lower proportion of CD8+ and NKT cells and a higher proportion of B cells, impaired cytokine production when stimulated ex vivo, and impaired ability of lymphocytes to proliferate compared with their lean counterparts. CONCLUSION: Obese pregnancy is associated with impaired cell-mediated immunity. Because perinatal infections can have serious maternal and fetal consequences, it is imperative to better understand these mechanistic underpinnings to optimize prevention and devise targeted therapy.

Effect of dietary supplementation with white button mushrooms on host resistance to influenza infection and immune function in mice.

Previously, we showed that mice fed white button mushrooms (WBM) had enhanced immune functions known to help the body's antiviral defence. In the present study, we tested whether WBM conferred protection against viral infection. Young (4-month-old) and old (22-month-old) C57BL/6 mice were fed a diet containing 0, 2 or 10 % WBM powder for 8 weeks. Mice were then infected with influenza Puerto Rico/8/34 (H1N1), and killed at day 0 (uninfected), 2, 5 or 7 post-infection. The primary outcomes of the study were viral titre and body weight. Secondary outcomes were natural killer (NK) cell activity, lymphocyte proliferation and cytokine production. The results showed that WBM did not affect viral titre, nor did it prevent infection-induced weight loss. WBM supplementation was found to enhance NK cell activity in old mice and to increase interferon (IFN)-γ production in young and old mice under naive (uninfected) conditions, but it had no such effect after infection. The lack of a mushroom supplementation effect on NK activity and concanavalin A-stimulated IFN-γ production after infection may explain the immune system's failure to reduce viral load and weight loss in mice after influenza infection. WBM supplementation, however, did induce changes in other aspects of the immune response: it significantly increased the production of T-helper type 2 cytokines IL-4 and IL-10 in uninfected mice and pro-inflammatory cytokines IL-1ß and TNF-α in infected mice. These mushroom-induced systemic changes, however, were not adequate to confer a protective effect against influenza infection.