Dairy Fat Consumptions Do Not Modulate Immune Functions in a Swine Model of Insulin Resistance: A Preliminary Analysis

Objectives Biomarkers of full-fat dairy consumption have been inversely associated with variables of insulin resistance (IR) and immune function. To understand the effect of consuming dairy fat per se on immune function in the context of IR, we used our established low birthweight (LBW) swine model of high fat diet induced IR to compare regular fat dairy products vs. low-fat dairy products and compared to a control high fat diet (CHF). We hypothesize that consuming a diet rich in dairy fat will improve immune function in the context of IR. Methods At 5 weeks of age, LBW piglets were randomized to consume one of the 3 experimental diets: 1) CHF, 2) HF supplemented with 3 servings high fat dairy (HFDairy) and 3) HF supplemented with 3 servings low fat dairy (LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF or standard pig grower diet (Chow). A total of 35 pigs (LBW-CHF n = 8, LBW-HFDairy n = 8, LBW-LFDairy n = 8, NBW-CHF n = 6, NBW-Chow n = 5) were fed for 7 weeks. At 12 weeks of age, pigs were euthanized for tissue and blood collections. Mitogen stimulations on peripheral blood mononuclear cells were conducted to assess immune responses. Results Results show that there were no statistical differences in IL-2, IL-10 and TNF-α levels after pokeweed mitogen (PWM, T and antigen presenting cell mitogen) and phytohaemagglutinin (PHA, T cell mitogen) stimulations between all LBW groups. However, IL-10 levels after PHA stimulation were found to be higher in NBW-Chow compared to LBW-CHF, LBW-HFDairy and LBW-LFDairy (all P < 0.05). Similarly, IL-2 levels after PWM stimulation were found to be higher in NBW-Chow compared to LBW-CHF and LBW-HFDairy (both P < 0.05) groups but not LBW-LFDairy. Conclusions Current data suggest that consumption of dairy products, regardless of the fat content, as little effect on immune function in the context of IR. However, we demonstrated that diet-induced IR piglets exhibit altered immune responses to a T cells mitogen, compared to NBW piglets. Funding Sources Agriculture Funding Consortium, NSERC Discovery Program, Dairy Farmers of Canada-Nutrition Research Program.

Hyperactive cytokine T-cell response is associated with immunosenescence in severe acute COVID-19 infection

COVID-19 is a disease caused by the novel SARS-CoV-2 coronavirus, originally classified as a severe acute respiratory syndrome coronavirus (SARS-CoV). The most severe cases of COVID-19 can progress to severe pneumonia with respiratory failure, septicemia, multiple organ failure and death. The severity of the disease is aggravated by the deregulation of the immune system causing an excessive initial inflammation including the cytokine storm, compring interleukins characteristic of the T-dependent adaptive response. In the present study we show that severe patients have high levels of T helper type-1 and type-2 cytokines, as well as VGEF. Furthermore, our show abnormal cytokine levels upon T-cell mitogen stimulation, in a non-polarized response profile. This response is not specific, given that the stimulus with the heterologous tuberculin antigen was able to induce high levels of cytokines compared to healthy controls, including the vascular endothelial growth factor VEGF, which promotes neoangiogenesis in physiological and pathophysiological conditions, caused by tissue hypoxia, and involved in a clonal exhaustion program in T cells. This can be decisive given our findings demonstrating for the first time a significantly increased frequency of late-differentiated CD8+ T cells characterized by critically shortened telomeres with particular phenotype (CD57+CD28-) in severe acute COVID-19 infection. These findings reveal that severe COVID-19 is associated with senescence of T cells, especially within the CD8+ T cell compartment and points to possible mechanisms of loss of clonal repertoire and susceptibility to recurrences of COVID-19 symptoms, due to viral relapse and reinfection events.

Comparative analysis of Mycobacterium tuberculosis-specific antigens and T-cell mitogen-stimulated interferon gamma production in hemodialysis patients and healthy individuals

Background The incidence of Tuberculosis (TB) is higher in patients undergoing chronic hemodialysis than in the general population; further, both the incidence and development of active TB from latent TB infection (LTBI) are considerably higher in patients undergoing hemodialysis than in any other group. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay is one of the most commonly used interferon gamma (IFN-γ) release assays (IGRAs) currently. We aim to know T-cell function of hemodialysis patients and the possible QFT false negatives. Methods In order to analyze the MTB-specific antigen-stimulated IFN-γ release in patients on hemodialysis, the QFT-GIT test was used in this study. A total of 84 hemodialysis patients and 52 healthy subjects were enrolled from Kosin University Gospel Hospital and Catholic University of Pusan, Busan, Republic of Korea; their whole blood samples were collected and used for the present study. Results The positivity results of the IGRAs in hemodialysis patients and normal subjects were 34/84 (40.4%) and 4/52 (7.6%), respectively. The mean value of MTB-specific antigen-stimulated IFN-γ in hemodialysis patients with LTBI and non-LTBI status in hemodialysis patients, healthy individuals were 1.85 IU/mL (4.44ng/mL) and 0.028 IU/mL (0.067 ng/mL) and 0.255 IU/mL (0.612 ng/mL) respectively. In addition, Of the 34 LTBI status in hemodialysis patients, 14 (41.2%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 20 (58.8%) had 10 or more T-cell mitogen-stimulated IFN-γ. Moreover, Of the 49 non-LTBI status in hemodialysis patients, 19 (38.8%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 30 (61.2%) showed T-cell mitogen-stimulated IFN-γ levels of 10 or more. On the other hand, there was no low level of T-cell mitogen-stimulated IFN-γ in the healthy individuals. Conclusion This reveals that T-cell function in hemodialysis patients was reduced as compared to the healthy individuals. Therefore, the cut-off value should be adjusted for the active TB high-risk group when using IGRA tests. The clinical manifestations of TB in patients on hemodialysis are quite non-specific, making timely diagnosis difficult, and delaying the initiation of curative treatment, delay being a major determinant of outcome.

Comparative Analysis of Mycobacterium Tuberculosis-Specific Antigens and T-Cell Mitogen-Stimulated Interferon Gamma Production in Hemodialysis Patients and Healthy Individuals

Background: The incidence of Tuberculosis (TB) is higher in patients undergoing chronic hemodialysis than in the general population; further, both the incidence and development of active TB from latent TB infection (LTBI) are considerably higher in patients undergoing hemodialysis than in any other group. The QuantiFERON-TB Gold In-Tube (QFT-GIT) assay is one of the most commonly used interferon gamma (IFN-γ) release assays (IGRAs) currently. We aim to know T-cell function of hemodialysis patients and the possible QFT false negatives.Methods: In order to analyze the MTB-specific antigen-stimulated IFN-γ release in patients on hemodialysis, the QFT-GIT test was used in this study. A total of 84 hemodialysis patients and 52 healthy subjects were enrolled from Kosin University Gospel Hospital and Catholic University of Pusan, Busan, Republic of Korea; their whole blood samples were collected and used for the present study.Results: The positivity results of the IGRAs in hemodialysis patients and normal subjects were 34/84 (40.4%) and 4/52 (7.6%), respectively. The median value of MTB-specific antigen-stimulated IFN-γ in hemodialysis patients with LTBI and non-LTBI status in hemodialysis patients, healthy individuals were 1.85 IU/mL (4.44ng/mL) and 0.028 IU/mL (0.067 ng/mL) and 0.255 IU/mL (0.612 ng/mL) respectively. In addition, Of the 34 LTBI status in hemodialysis patients, 14 (41.2%) had T-cell mitogen-stimulated IFN-γ levels of 10 or less, and 20 (58.8%) had 10 or more T-cell mitogen-stimulated IFN-γ. Moreover, Of the 49 non-LTBI status in hemodialysis patients, 19 (38.8%) and 30 (61.2%) respectively. On the other hand, there was no low level of T-cell mitogen-stimulated IFN-γ in the healthy individuals.Conclusion: This reveals that T-cell function in hemodialysis patients was reduced as compared to the healthy individuals. Therefore, the cut-off value should be adjusted for the active TB high-risk group when using IGRA tests. The clinical manifestations of TB in patients on hemodialysis are quite non-specific, making timely diagnosis difficult, and delaying the initiation of curative treatment, delay being a major determinant of outcome.

The Nod2 Agonist Muramyl Dipeptide Cooperates with the TLR4 Agonist Lipopolysaccharide to Enhance IgG2b Production in Mouse B Cells

Many studies have shown that Toll-like receptors (TLRs) and Nod-like receptors (NLRs) were expressed in B cells and their signaling affects B cell functions. Nonetheless, the roles played by these receptors in B cell antibody (Ab) production have not been completely elucidated. In the present study, we examined the effect of the Nod2 agonist muramyl dipeptide (MDP) in combination with the TLR4 agonist lipopolysaccharide (LPS), a well-known B cell mitogen, on B cell viability, proliferation, and activation, and Ab production by in vitro culture of purified mouse spleen resting B cells. MDP combined with LPS to reinforce B cell viability, proliferation, and activation. Moreover, MDP enhanced LPS-induced IgG2b production, germline γ2b transcript (GLTγ2b) expression, and surface IgG2b expression. In an experiment with Nod2- and TLR4-deficient mouse B cells, we observed that the combined effect of MDP and LPS is dependent on Nod2 and TLR4 receptors. Furthermore, the combined effect on B cell viability and IgG2b switching was not observed in Rip2-deficient mouse cells. Collectively, this study suggests that Nod2 signaling enhances TLR4-activated B cell proliferation, IgG2b switching, and IgG2b production.

Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells

Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment.

Metformin counteracts the effects of FSH on rat Sertoli cell proliferation

Metformin (MET) is one of the most widely used anti-hyperglycemic agents for treating patients with type 2 diabetes and it has started to be used in pediatric population at ages when Sertoli cells are still proliferating. It is well known that follicle-stimulating hormone (FSH) is the major Sertoli cell mitogen. The aim of the study is to investigate a possible effect of MET, which has been shown to have anti-proliferative properties, on FSH regulation of postnatal Sertoli cell proliferation and on the molecular mechanisms involved in this regulation. The present study was performed in eight-day-old rat Sertoli cell cultures. The results obtained show that MET in the presence of FSH increases phosphorylated acetyl-CoA carboxylase and decreases phosphorylated p70S6K levels. Moreover, we show that MET decreases FSH-stimulated Sertoli cell proliferation, and this decrease is accompanied by a reduction in FSH-stimulated Ccnd1 and Ccnd2 expression and an increase in cell cycle inhibitor p21Cip expression. Altogether, these results suggest that MET can, at least in part, counteract the effect of FSH on postnatal Sertoli cell proliferation.