Immune Modulatory Effects Research Articles

Impact of COVID-19, lockdowns and vaccination on immune responses in a HIV cohort in the Netherlands

IntroductionDuring the COVID-19 pandemic, major events with immune-modulating effects at population-level included COVID-19 infection, lockdowns, and mass vaccinations campaigns. As immune responses influence many immune-mediated diseases, population scale immunological changes may have broad consequences.MethodsWe investigated the impact of lockdowns, COVID-19 infection and vaccinations on immune responses in the 2000HIV study including 1895 asymptomatic virally-suppressed people living with HIV recruited between October 2019 and October 2021. Their inflammatory profile was assessed by targeted plasma proteomics, immune responsiveness by cytokine production capacity of circulating immune cells, and epigenetic profile by genome-wide DNA methylation of immune cells.ResultsPast mild COVID-19 infection had limited long-term immune effects. In contrast, COVID-19 vaccines and especially lockdowns significantly altered both the epigenetic profile in immune cells at DNA methylation level and immune responses. Lockdowns resulted in a strong overall exaggerated immune responsiveness, while COVID-19 vaccines moderately dampened immune responses. Lockdown-associated immune responsiveness alterations were confirmed in 30 healthy volunteers from the 200FG cohort that, like the 2000HIV study, is part of the Human Functional Genomics Project.DiscussionOur data suggest that lockdowns have unforeseen immunological effects. Furthermore, COVID-19 vaccines have immunological effects beyond anti-SARS-CoV-2 activity, and studies of their impact on non-COVID-19 immune-mediated pathology are warranted.

NK cells-derived extracellular vesicles potency in the B cell lymphoma biotherapy

IntroductionExtracellular vesicles of Natural Killer cells (NKEV) exert an antitumor effect towards hematopoietic and solid tumors and have an immune modulating effect, suggesting a promising role in immune and biotherapy. In this study, a continuation of our former works, we demonstrated a network by mass spectrometry analysis between NKEV protein cargo and antitumor effects. Human healthy NKEV, both exosomes and microvesicles, have a significant and direct cytotoxic effect against human B cell lymphoma in in vitro and in vivo conditions.MethodsWe isolated extracellular vesicles from in vitro amplified healthy human NK cells and their treatment efficacy was monitored by cytometry analyses, in vivo MRI/MRS measurements, ex vivo MRS analyses and immunohistochemistry.ResultsWe observed a remarkable NKEV cytotoxic effect, mainly by apoptosis, on B cell lymphoma in vitro when exosomes and microvesicles were administered simultaneously. In vivo results showed metabolic alterations in SCID mice xenografts after NKEV treatment, associated with a significant reduction of tumor growth (64%). In the in vivo1H MR spectra we found a significant increase in the tumor lipid/lactate and in taurine signals, both considered as apotosis markers. Ex vivo lymphoma metabolomics revealed a significant increase in fatty acid (FA) pool and decrease in unsaturated and mono-unsaturated FA in treated groups, as compared to control one, thus suggesting an alteration of tumor homeostasis. Immunohistochemistry analyses confirmed the reduction of B-cell lymphoma proliferation rate, as well as the induction of apoptosis following the NKEV treatment. ConclusionsThis study underscore the importance of NKEV as a novel biological acellular tool for B-cell lymphoma treatment, probably having a greater effect on combined treatment regimens. These nanovesicles have an extraordinary potential in innovative cancer immunotherapy, representing a safe and efficient tool naturally circulating in healthy individuals and ready to maintain the immune homeostasis, and therefore a good organism healthy state.

Effects of probiotics on clinical manifestations and inflammatory markers in HTLV-1-associated myelopathy/tropical spastic paraparesis: A triple blind randomized, placebo controlled trial

Human T-lymphotropic virus type 1 (HTLV-1), leads to adult T-cell lymphoma/leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals. The virus promotes inflammation, a major factor in chronic disease progression. Probiotics' immune modulation and anti-inflammatory effects present a potential therapeutic intervention for HTLV-1-related conditions. This study investigates the impact of probiotics on both clinical manifestations and inflammatory markers in HAM/TSP patients.Conducted at the HTLV-1 clinic of Ghaem Hospital (Mashhad, Iran) between 2019 and 2020, this study randomized 40 HAM/TSP patients into two groups: an intervention group receiving 500 mg LactoCare capsules twice daily and a control group receiving placebo capsules of identical appearance for 12 weeks. Baseline and follow-up assessments included muscle strength, spasticity, motor disability, urinary disturbance, and serum levels of IL-10, IL-4, and IFN-γ (measured by ELISA). Post-intervention analysis revealed no significant differences between intervention and control groups in muscle strength, spasticity, and motor disability. However, significant improvement was observed in the intervention group regarding urinary symptoms after 12 weeks of initiation of intervention (P = 0.003). No significant changes were detected in serum levels of IL-10, IL-4, and IFN-γ between the two groups. The probiotics showed positive effects on urinary symptoms in HTLV-1-associated myelopathy/tropical spastic paraparesis patients but did not significantly impact other clinical or paraclinical parameters within the 12-week study period. These findings suggest that probiotics may offer symptomatic relief for some symptoms of HTLV-1-associated myelopathy/tropical spastic paraparesis patients.

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.

Small intestinal derived Prevotella histicola simulates biologic as a therapeutic agent

A role of gut microbiome in pathogenesis as well as response to treatment is documented in rheumatoid arthritis. Using a novel duodenal derived Prevotella histicola strain MCI 001, we have shown that it suppresses disease progression in a collagen-induced arthritis (CIA), a model for rheumatoid arthritis (RA) using humanized mice expressing HLA-DQ8 gene in the absence of endogenous class II genes. Here we compared efficacy of P. histicola MCI 001 with tumor necrosis factor inhibitor (TNFi) for treating arthritis. DQ8 arthritic mice treated with P. histicola by oral gavage or TNFi, were compared for disease onset, incidence and severity. We demonstrate that oral treatment with P. histicola mimics treatment with TNFi in arthritic DQ8 mice. A pangenome comparison of our P. histicola MCI 001 with its closest available neighbors depicted it as a novel strain with unique gene sequences that may contribute to immune modulatory effects. Notably, it possesses a unique sequence of an outer membrane protein, BtuB, which is involved in vitamin B12 transport. Our data indicate that P. histicola MC001 is an attractive candidate to prevent the progression of disease in RA patients with ongoing disease.

Cigarette smoke-induced disordered microbiota aggravates the severity of influenza A virus infection.

Cigarette smoke (CS) promotes the development of chronic pulmonary disease and has been associated with increased risk for influenza-related illness. Here, we directly addressed the impact of CS disordered microbiota on the severity of influenza A virus (IAV) infection. Specific and opportunistic pathogen-free (SOPF) C57BL/6J mice were exposed to CS or room air (RA) for 5.5 months. Each exposed mouse was then cohoused with a group of recipient germ-free (GF) mice for 1 month for microbial transfer. Colonized GF mice were then infected intranasally with IAV and disease development was monitored. Upper and lower airway and fecal microbiota were longitudinally investigated by 16S rRNA gene sequencing and bacterial cultures in donor and recipient mice. The bacterial family Streptococcaceae accounted for the largest difference between CS- and RA-exposed microbiota in the oropharynx. Analysis of the oropharynx and fecal microbiota indicated an efficient transfer to coprophagic recipient mice, which replicated the differences in microbiota composition observed in donor mice. Subsequent IAV infection revealed significantly higher weight loss for CS microbiota recipient mice at 8-10 days post infection (dpi) compared to control recipient mice. In addition, H1N1 infection inflicted substantial changes in the microbiota composition, especially at days 4 and 8 after infection. In conclusion, mice with a CS-associated microbiota suffer from higher disease severity upon IAV infection compared to mice colonized with a normal SOPF microbiota. Our data suggest that independently of CS exposure and concomitant structural lung damage, microbial distortion due to CS exposure may impact the severity of IAV disease course.IMPORTANCEIt has been reported that chronic exposure to CS is associated with a disordered microbiota composition. In this study, we colonized germ-free (GF) mice with the microbiota from SOPF mice which were chronically exposed to CS or RA. This allowed disentangling the effect of the disordered microbiota from the immune-modulating effects of actual CS exposure. We observed a successful transfer of the microbiotas after cohousing including specific microbiota differences induced by CS exposure in formerly GF mice, which were never exposed to CS. We then investigated the effects of IAV infection on the disease course and microbiotas of formerly GF mice. We found that mice with CS-associated microbiota reveal worse disease course compared to the control group. We hypothesize that CS-induced disordering of the microbiota may, indeed, impact the severity of influenza A disease.

Enhanced Bioavailability and Immune Benefits of Liposome-Encapsulated Vitamin C: A Combination of the Effects of Ascorbic Acid and Phospholipid Membranes

The bioavailability of vitamin C, or ascorbic acid, depends on limiting transport mechanisms that may be bypassed by liposome-encapsulation. The goal for this study was to evaluate the uptake, antioxidant, and immune-modulating effects of liposome-encapsulated vitamin C (LEC) using Lypo-Spheric® technology, compared to three controls: ascorbic acid (AA), the phospholipid fraction composing the liposome, and placebo. A double-blinded placebo-controlled cross-over study design involved twelve healthy participants attending four clinic visits. At each visit, a baseline blood draw was performed, followed by consumption of 1 g LEC, 1 g AA, the phospholipid component of LEC, or placebo. Additional blood draws were performed at 2, 4, and 6 h. Consuming LEC and AA increased blood levels of vitamin C; the levels were significantly higher after consuming LEC at all timepoints when compared to AA (p < 0.01). LEC consumption increased serum antioxidant capacity (p < 0.01 at 2 h) and protection. Consuming LEC increased IFN-γ levels at 6 h, while consuming the phospholipid fraction rapidly decreased inflammatory cytokines IL-6, MCP-1, and MIP-1α at 2 h. Consuming LEC provided enhanced vitamin C bioavailability and antioxidant protection compared to AA. Consuming the phospholipids had anti-inflammatory effects. The results suggest that LEC provides antioxidant and immune benefits above AA, useful in preventive medicine.

IMMUNOLOGICAL INFLUENCES OF THE CALENDULA OFFICINALIS TEA TREATMENT IN DAIRY COWS

The influence of environmental factors and growth technologies has a substantial impact on health and immunization of animals following antigenic stimulation, so the way vaccine protection is provided cannot be evaluated outside the habitat framework. Medicinal plants have often been used to augment the immune response in humans or animals. In the case of bovine, due to technologies where access to grazing is increasingly available, the animals can benefit directly from the adjuvant influences of medicinal plants in the spontaneous flora. This research aimed at quantifying the effects of orally administered Calendula officinalis aqueous extract (tea) on the innate and adaptive cell-mediated immunity under vaccination conditions, trying to define its immune modulating effect in young bovine. For that, an experiment was performed by administering Calendula officinalis tea perorally to a batch of bovine vaccinated with a complex vaccine for a week post vaccination. On days 0, 7 and 14, in vitro leukocytes blast transformation, and the stress level expressed by the N / L ratio were determined. Vaccination is a stressful event for animals, however, the animals subjected to tea treatment had a higher initial N/L index, which decreased considerably, supporting the decrease in the level of stress by administering marigold tea. The in vitro capacity of the mononuclear cells sampled from the marigold tea treated group was higher towards the standard mitogens PHA M and LPS (p

IMMU-50. IMPACT OF SARS-COV-2 MRNA VACCINES ON PD-L1 EXPRESSION IN INTRACRANIAL TUMORS

Abstract Although immune checkpoint inhibitor (ICI) effectiveness is correlated with intra-tumoral PD-L1 expression, there are no clinically available methods to improve sensitivity to ICIs by modulating PD-L1 expression. mRNA vaccines stimulate robust interferon-dependent innate immune activation leading to four-fold increases in PD-L1 expression on peripheral and intratumoral myeloid cells and enhanced sensitivity to immune checkpoint blockade in preclinical models (Sayour, Grippin, et al., NanoLetters, 2018; Mendez-Gomez, et al., Cell, 2024). We hypothesized that mRNA vaccines targeting SARS-COV-2 would similarly enhance PD-L1 expression in intracranial tumors. To test this hypothesis, we utilized institutional databases to identify 5,524 patients at our institution with pathology reports including the term “PD-L1” from August 2020 to November 2023. Pathological data and dates of SARS-COV-2 vaccination were compiled for each patient. Across the entire cohort (n=5,524), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a 55% increase in mean tumor proportion score (TPS) (14% vs 8.9%, p=0.029). In the subset of patients with intracranial tumors (n=187), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a massive increase in TPS (57% vs 7.2%, p<0.001). To evaluate the impact of this change on clinical outcomes with immunotherapy, we utilized a second institutional database to assemble a cohort of patients with Stage IV melanoma with intracranial metastasis treated with immune checkpoint blockade during the period August 2020 through November 2023. Patients who received a SARS-COV-2 vaccine within 100 days of initiation of ICI (n=10) exhibited numerically improved overall survival compared to those without SARS-COV-2 mRNA vaccine (n=38) (HR 0.50, 95% CI 0.22-1.2, p=0.06). Median overall survival was 545 days among patients without COVID mRNA vaccination and was not met among those with COVID mRNA vaccination. This data supports further investigation of the immune modulating effect of SARS-COV-2 mRNA vaccines in patients with intracranial tumors treated with immune checkpoint blockade.

Mechanism of the KIAA1429/KLF1/PD-L1 Axis in Regulating Immune Escape in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC), accounting for approximately 80% of lung cancer cases, remains the leading cause of cancer-related mortality. Immune evasion is a critical challenge in NSCLC, contributing to poor treatment outcomes. This study investigates the role of KIAA1429 in immune evasion, aiming to identify novel therapeutic targets and provide a theoretical basis for NSCLC treatment. NSCLC cell lines were cultured to assess the expression of KIAA1429, KLF transcription factor (KLF1), and programmed cell death ligand 1 (PD-L1). Co-culture experiments were conducted with peripheral blood mononuclear cells (PBMCs) to evaluate cytotoxicity, CD8+T cell proportions, and levels of interferon-gamma (IFN-γ)/interleukin (IL)-10/IL-2. Additionally, N6-methyladenosine (m6A) modification in NSCLC cells, m6A enrichment on KLF1, and KLF1 mRNA stability were analyzed. Results showed increased expression of KIAA1429 and KLF1 in NSCLC cells. Knockdown of KIAA1429 inhibited NSCLC cell proliferation, enhanced PBMC cytotoxicity and CD8+T cell activation, increased IFN-γ and IL-2 levels, and decreased IL-10 levels. Mechanistically, KIAA1429 stabilized KLF1 mRNA level through m6A modification, promoting both KLF1 and PD-L1 expression. Overexpression of KLF1 or PD-L1 reversed the immune-modulating effects of KIAA1429 knockdown. In conclusion, KIAA1429 facilitates immune evasion in NSCLC by stabilizing KLF1 mRNA and upregulating PD-L1 expression.

Cholecystokinin and gastrin as immune modulating hormones: Implications and applications

Cholecystokinin (CCK) and gastrin are gastrointestinal hormones traditionally recognised for their roles in digestion. However, it has been recognised that these hormones may also modulate immune function. Here, we examine the immune-modulating effects of CCK and gastrin, and explore the functional significance of this dual role. In addition to the direct effect of these hormones on immune cell function, we discuss why hormones that regulate complex physiological and behavioural aspects of digestion might also influence immune responses. Notably, recent findings highlight the importance of these hormones in promoting a tolerogenic hepatic environment, particularly as the liver encounters gut-derived inflammogens following a meal. Additionally, the neuro-immune crosstalk mediated by CCK suggests that this hormone may influence immune responses indirectly via the gut-brain axis, especially in the context of infection or inflammation. Furthermore, the role of CCK in inducing feeding cessation and satiety appears to be repurposed during sickness behaviour, such as the loss of appetite during infection. Collectively, these observations suggest that nutritional strategies, including permissive underfeeding or fasting, could have important clinical implications. A deeper understanding of the dual roles of CCK and gastrin in digestion and immunity may pave the way for novel therapeutic approaches that leverage these pathways for improved disease management and treatment outcomes.

Influence of blood pressure targets on inflammation and associations between inflammatory markers and vasopressor usage after cardiac arrest - a substudy of a randomized clinical trial

Abstract Background Following resuscitation from cardiac arrest, a profound systemic inflammatory response may develop. In observational studies of critically ill patients an association between levels of inflammation and vasopressor usage has been found. Higher levels of inflammation may lead to higher vasopressor needs due to vasoplegia and cardiac dysfunction, however, catecholamines, including vasopressors also have immune modulatory effects. In the Blood Pressure and Oxygenation Targets in Post resuscitation Care (BOX) trial patients were randomized to a high or low blood pressure target, and vasopressor usage was increased in the high blood pressure target group. Therefore, the inflammatory response evoked by cardiac arrest, may have been altered by differences in vasopressor usage according to blood pressure target in this trial. Purpose To determine if differences in vasopressor and inotropy usage associated with randomization to a high compared to a low blood pressure target affects the inflammatory response after OHCA, and to investigate the association between inflammation and vasopressor and inotropy usage. Methods In the BOX trial, comatose OHCA patients with a presumed cardiac etiology were randomized to a blinded intervention of either a high (77mmHg) or a low blood pressure target (63mmHg). The inflammatory markers of leukocytes and CRP were measured at 0, 24, 48, and 72 hours. The average Vasoactive-Inotropic Score (VIS) was determined during initial 72 hours. The associations between average CRP, leukocytes, and VIS during initial 72 hours were determined by Spearman’s correlation analysis. Results The BOX trial included 789 resuscitated comatose OHCA patients, and 788 patients had at least 1 measurement of leukocytes and CRP. The median age was 64 (IQR 54-73), females constituted 19%, 1 year mortality was 36%. There was no difference in leukocytes and CRP at admission between the high and low blood pressure target groups (Figure 1). Leukocytes were slightly higher at 24 hours (p<0.01) in the high blood pressure target group, but no group differences were found at 48 and 72 hours, and CRP levels did not differ at 24, 48, or 72 hours. The average VIS was 19 (11-32) and 11 (5-19), p<0.01, in the two groups, with VIS being consistently higher at all timepoints beyond ICU admission (all p<0.01, data not shown) in patients with a high blood pressure target. Both average CRP and leukocytes were weakly correlated with average VIS at 0-72 hours for both blood pressure targets, r=0.17 and r=0.20, respectively for a high target (both p<0.01), and r=0.17 and r=0.20, respectively for a low target (both p<0.01). Conclusions In conclusion, increased vasopressor and inotropy usage in this randomized, blinded study of blood pressure targets after OHCA, did not lead to clinically relevant changes in inflammation. Inflammatory markers and VIS were correlated to a similar degree for both blood pressure targets.Figure 1, LeukocytesFigure 2, CRP

Growth, development and commercial traits of sturgeon fish species under industrial fi sh farming conditions when use the feed additive Abiotonic

Artificial fish farming including commercial sturgeon farming using highly nutritious balanced feeds is nothing less than a strategically important area in Russian agriculture. In recent years, methods for increasing animal productivity using highly biologically active additives both natural and artifi cial, which have a growth-stimulating, protective and immune-modulating eff ect on the body of animals at various stages of development, have found wide application. These include the feed additive Abiotonic. In the literature studied by us, we found no information on the eff ect of the feed additive Abiotonic on the growth, development and livability of sturgeon fi sh, as well as on the quality indicators of the resulting fi sh products. In this regard, studies aimed at studying the eff ect of the vitamin-microelement growth immunostimulant Abiotonic on the productivity of sturgeon fi sh are relevant. The purpose of the research was to study the growth, development and commercial traits of sturgeon fi sh species under industrial fi sh farming conditions using the feed additive Abiotonic. The research established the optimal amount of the feed additive Abiotonic for use in the diets of the hybrid Russian and Siberian sturgeon inder industrial fi sh farming conditions. Thus, when rearing sturgeon fi sh with high productive and commercial traits, as well as with low feed costs per unit of fi sh weight gain and the cost of fi sh products under industrial conditions, we recommend that fish farms use the feed additive Abiotonic in the diets of sturgeon fi sh in the mount of 1.0 ml per 1.0 kg of fi sh body weight.

Some Applications of Hericium erinaceus Mushrooms: A Review

The Lion's Mane mushroom, which has the scientific name Hericium erinaceus, can be defined as a medicinal fungus type. For very long time, it has been utilized in the conventional medicine in Asia for a variety of purposes. In the past few years, there had been a great deal of interest directed towards potential benefits to the health, which could be provided by this unique type of mushroom in particular, when it comes to the treatment of various diseases. The concentration will be focused on examining the way that Hericium erinaceus as well as its bioactive elements could be utilized for therapeutic purposes within the area od disease control. This review states the possible Hericium erinaceus advantages in cases that are related to some health issues, such as metabolic problems, gastrointestinal diseases, neurodegenerative disorders, and immune system problems. In addition to that, the present paper discusses the work that is used for providing the therapeutic effects. It is stated that some of the characteristics of the Hericium erinaceus include having anti-inflammatory, neuro-protective, anti-oxidant, and immune-modulatory effects. Even though more studies are needed for detailed understanding of all the mechanisms that are involved in its activities, presenting evidences that strongly suggest possible Hericium erinaceus uses as one of the natural cures for a variety of illnesses, it is known as well in some cases as lion's mane mushroom, which fungus type that comes with extensive history and many potential advantages. As a result of its distinctive morphology, including bio-active compounds, in addition to its conventional uses have combined to the generation of much interest in a variety of areas. More research is needed for full understanding of the way that it works for the therapeutic applications and its potential implementations in the area of nutrition, cooking, and medicine. The cultivation of Hericium erinaceus might be viewed as an activity of conservation and business production.

Clinical and experimental investigations into the immune modulatory effects of Qianjinba polysaccharides on a rheumatoid arthritis mouse model: in vivo and in vitro studies

Clinical and experimental investigations into the immune modulatory effects of Qianjinba polysaccharides on a rheumatoid arthritis mouse model: in vivo and in vitro studies

Immune Implications of Cholesterol-Containing Lipid Nanoparticles.

The majority of clinically approved nanoparticle-mediated therapeutics are lipid nanoparticles (LNPs), and most of these LNPs are liposomes containing cholesterol. LNP formulations significantly alter the drug pharmacokinetics (PK) due to the propensity of nanoparticles for uptake by macrophages. In addition to readily engulfing LNPs, the high expression of cholesterol hydroxylases and reactive oxygen species (ROS) in macrophages suggests that they will readily produce oxysterols from LNP-associated cholesterol. Oxysterols are a heterogeneous group of cholesterol oxidation products that have potent immune modulatory effects. Oxysterols are implicated in the pathogenesis of atherosclerosis and certain malignancies; they have also been found in commercial liposome preparations. Yet, the in vivo metabolic fate of LNP-associated cholesterol remains unclear. We review herein the mechanisms of cellular uptake, trafficking, metabolism, and immune modulation of endogenous nanometer-sized cholesterol particles (i.e., lipoproteins) that are also relevant for cholesterol-containing nanoparticles. We believe that it would be imperative to better understand the in vivo metabolic fate of LNP-associated cholesterol and the immune implications for LNP-therapeutics. We highlight critical knowledge gaps that we believe need to be addressed in order to develop safer and more efficacious lipid nanoparticle delivery systems.

Priming Mesenchymal Stem Cells with Lipopolysaccharide Boosts the Immunomodulatory and Regenerative Activity of Secreted Extracellular Vesicles

Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as an alternative to live-cell administration for Acute Respiratory Distress Syndrome (ARDS). MSC-EVs can be chiefly influenced by the environment to which the MSCs are exposed. Here, lipopolysaccharide (LPS) priming of MSCs was used as a strategy to boost the natural therapeutic potential of the EVs in acute lung injury (ALI). Methods: The regenerative and immunemodulatory effect of LPS-primed MSC-EVs (LPS-EVs) and non-primed MSC-EVs (C-EVs) were evaluated in vitro on alveolar epithelial cells and macrophage-like THP-1 cells. In vivo, ALI was induced in adult male rats by the intrapulmonary instillation of HCl and LPS. Rats (n = 8 to 22/group) were randomized to receive a single bolus (1 × 108 particles) of LPS-EVs, C-EVs, or saline. Lung injury severity was assessed at 72 h in lung tissue and bronchoalveolar lavage. Results: In vitro, LPS-EVs improved wound regeneration and attenuated the inflammatory response triggered by the P. aeruginosa infection, enhancing the M2 macrophage phenotype. In in vivo studies, LPS-EVs, but not C-EVs, significantly decreased the neutrophilic infiltration and myeloperoxidase (MPO) activity in lung tissue. Alveolar macrophages from LPS-EVs-treated animals exhibited a reduced expression of CXCL-1, a key neutrophil chemoattractant. However, both C-EVs and LPS-EVs reduced alveolar epithelial and endothelial permeability, mitigating lung damage. Conclusions: EVs from LPS-primed MSCs resulted in a better resolution of ALI, achieving a greater balance in neutrophil infiltration and activation, while avoiding the complete disruption of the alveolar barrier. This opens new avenues, paving the way for the clinical implementation of cell-based therapies.

Immune modulatory effects of tulathromycin, gamithromycin, and oxytetracycline in cattle

Certain classes of antibiotics, including tetracyclines and macrolides, are known to exert immune suppressive effects in other species but the immune modulatory effects of these antibiotics have not been previously studied in cattle. To address this question, we investigated the effects of oxytetracycline, gamithromycin, and tulathromycin on T cell and macrophage responses to activation, using in vitro assays. In addition, we assessed the impact of these antibiotics on T cell responses in vivo following treatment of healthy cattle with currently recommended doses of each of the three antibiotics. We found that all 3 antibiotics markedly suppressed T cell proliferation in vitro at relevant therapeutic drug concentrations and significantly suppressed macrophage activation responses to LPS. In cattle treated with a single dose of each antibiotic, we observed significant suppression of T cell proliferation and cytokine production beginning as early as 6 h after administration, with increasing immune suppression observed at 48 h. Taken together, these results indicate that commonly used antibiotics in cattle exert significant immune modulatory activity, in addition to their antimicrobial activity. These off-target effects should be considered when using antibiotics for prophylaxis or metaphylaxis in high-risk dairy or beef cattle (192 words).

Staphylococcus aureus SaeRS impairs macrophage immune functions through bacterial clumps formation in the early stage of infection

The Staphylococcus aureus (S. aureus) SaeRS two-component system (TCS) regulates over 20 virulence factors. While its impact on chronic infection has been thoroughly discussed, its role in the early stage of infection remains elusive. Since macrophages serve as the primary immune defenders at the onset of infection, this study investigates the influence of SaeRS on macrophage functions and elucidates the underlying mechanisms. Macrophage expression of inflammatory and chemotactic factors, phagocytosis, and bactericidal activity against S. aureus were assessed, along with the evaluation of cellular oxidative stress. SaeRS was found to impair macrophage function. Mechanistically, SaeRS inhibited NF-κB pathway activation via toll-like receptor 2 (TLR2). Its immune-modulating effect could partially be explained by the strengthened biofilm formation. More importantly, we found SaeRS compromised macrophage immune functions at early infection stages even prior to biofilm formation. These early immune evasion effects were dependent on bacterial clumping as cytokine secretion, phagocytosis, and bactericidal activity were repaired when clumping was inhibited. We speculate that the bacterial clumping-mediated antigen mask is responsible for SaeRS-mediated immune evasion at the early infection stage. In vivo, ΔsaeRS infection was cleared earlier, accompanied by early pro-inflammatory cytokines production, and increased tissue oxidative stress. Subsequently, macrophages transitioned to an anti-inflammatory state, thereby promoting tissue repair. In summary, our findings underscore the critical role of the SaeRS TCS in S. aureus pathogenicity, particularly during early infection, which is likely initiated by SaeRS-mediated bacterial clumping.

Corticosteroid-induced bradycardia following high-dose methylprednisolone administration: a case report

Introduction: Besides their wide use in the clinical field due to their anti-inflammatory and immune-modulating effect, corticosteroids still have a lot of adverse effects. The most common adverse effects are hyperglycemia, hypertension, osteoporosis, psychosis, immunosuppression, weight gain, and hyperlipidemia. Another important side effect is cardiac arrhythmias. Case presentation: We report a case of a 43-year-old woman with multiple sclerosis who developed symptomatic bradycardia after 3 days of treatment with a high dose of methylprednisolone. The patient received a dose of atropine and her bradycardia resolved after 36 h of stopping methylprednisolone. Discussion: While tachyarrhythmias are more common, bradyarrhythmias such as bradycardia and premature atrial or ventricular contraction are rare but crucial to be considered. Conclusion: Corticosteroid-induced bradycardia is usually in sinus rhythm and has an unknown etiology, possibly occurring at high and low doses. The majority of cases in the literature were asymptomatic and resolved spontaneously.