Immune Modulatory Effects Research Articles

Different types of algae beneficial for bone health in animals and in humans – A review

Algae have long been recognized as a valuable source of nutrients and minerals. Recent studies suggest that diverse types of algae may provide benefits for bone health in animals and humans. This review article provides an overview of the several types of algae that have been found to be beneficial for bone health, including red, green, and brown algae and contain varying amounts of minerals such as calcium, magnesium, and phosphorus, essential for the development and maintenance of healthy bones. In addition to these minerals, algae contain bioactive compounds such as polysaccharides, polyphenols, and carotenoids, having antioxidant and anti-inflammatory properties that may support bone health. Studies suggest that the consumption of algae or algae-derived supplements may improve bone density and reduce the risk of osteoporosis in both animals and humans. Algae-based supplements have been found to have other health benefits, including immune system modulation, anti-cancer properties, and antiviral effects. While algae may hold promise as a natural source of bone-boosting nutrients, more research is needed to fully understand the mechanisms behind their effects on bone health and to determine optimal dosages for supplementation. Overall, the findings of this review suggest that algae are a promising dietary supplement for promoting bone health in animals and humans.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3months, achieving complete B cell depletion within 2weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.

Amivantamab in synergy with pembrolizumab effectively eradicated EGFRHIGHMETHIGH tumor subcluster in the tumor microenvironment of head and neck squamous cell carcinoma and overcame resistance against anti-PD-1 immunotherapy.

Immune Modulatory Effects of Mesenchymal Stem Cells Mediated by Lymphocyte Recruitment

Immune Modulatory Effects of Mesenchymal Stem Cells Mediated by Lymphocyte Recruitment

Prospective, Randomized, Double-Blind Parallel Group Nutritional Study to Evaluate the Effects of Routine Intake of Fresh vs. Pasteurized Yogurt on the Immune System in Healthy Adults.

The immune system is affected by the dietary products humans intake. Immune system regulation by nutrition has uses in the clinical context, but it can also benefit healthy populations by delaying or preventing the emergence of immune-mediated chronic illnesses. In this study, the purpose was to describe and compare the modulator effects on the immune system of the routine ingestion of fresh vs. pasteurized yogurt. A unicentral, prospective, randomized, double-blind, parallel group 8-week nutritional study was carried out comparing the ingestion of 125 g of the products in healthy adults three times a day. A complete battery of in vitro tests on the activity of the immune system, processes and phenomena was performed. Exclusive immune-modulatory effects of fresh yogurt with respect to base line were found in terms of increased systemic IgM (primary immune responses), increased synthesis of IFN-gamma upon stimulation (Th1) and increased peripheral T cells (mainly "naive" CD4s). In the three interventions, we observed an increased phagocytic activity and burst test in granulocytes, together with increased secretion of IL-6, IL-1 β and IL-8 (pro-inflammatory) and increased CD16 expression (FcR favoring phagocytosis) in granulocytes. Overall, it is concluded that regardless of bacteria being alive or thermally inactivated, yogurt has common effects on the innate system, but the presence of live bacteria is necessary to achieve a potentiating effect on the specific immune response.

LGG-46. MEKI WITH MIRDAMETINIB: EXPLORING ADAPTIVE SIGNALING PATHWAY DYNAMICS AND IMMUNE MODULATION IN PEDIATRIC GLIOMAS

Abstract INTRODUCTION Glial neoplasms are among the most common types of solid tumors in children. The mitogen-activated protein kinase (MAPK) pathway is implicated in glioma tumorigenesis. Drugs targeting this pathway hold promise as novel therapy for this disease. Vertical inhibition of the MAPK pathway has been linked to increased inflammation in several other cancers but similar exploration in pediatric brain tumors is limited. Within the MAPK pathway, MEK plays a significant role as a modulator of ERK phosphorylation. This study investigates the therapeutic potential of the MEK inhibitor, Mirdametinib, and evaluates the drugs’ capacity to induce tumor-intrinsic inflammation by characterizing changes in PD-L1 expression and proliferation in a panel of pediatric glial neoplasms. METHODS Three cell lines were included in the panel (Res186, Res259, SF188) and were treated with Mirdametinib for 3, 5, or 7 days. P-ERK expression, analyzed by western blot, verified successful inhibition of MEK by Mirdametinib. The CCK8 cytotoxic assay was utilized to determine the drug’s 50% inhibitory concentration as well as its direct effects on cell viability. Changes in Ki67 expression assessed by flow cytometry further characterized Mirdametinib’s effects on cell proliferation. Flow cytometry was also utilized to measure changes in PD-L1 expression following treatment. RESULTS Despite minimal effects on proliferation as measured by Ki67 and CCK8, expression of P-ERK verifies successful inhibition of MEK. Western blot data also reveals increased Pi3K/AKT pathway activity in SF188 groups treated with Mirdametinib. FACS data for SF188 also demonstrates increased PD-L1 expression in response to treatment. CONCLUSIONS Data suggests that, in response to MEKi, gliomas utilize compensatory growth mechanisms through Pi3K/AKT signaling. Findings also point to immune-modulatory effects of MEKi. Supporting results in ongoing experiments are expected to further our understanding of these mechanisms and may help inform effective combination treatment strategies for pediatric gliomas.

Venetoclax Induces BCL-2-Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti-PD-1 Checkpoint Blockade.

The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T cells (Treg), which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediated Treg plasticity toward a TH17-like Treg phenotype, resulting in increased IL17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.

Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease

BackgroundThe pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PurposeThis study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). MethodsHigh-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. ResultsA total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. ConclusionXKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

A systematic review and expert Delphi Consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology

BackgroundDupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. ObjectiveTo perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. MethodsA systematic review of the literature was performed, and an expert Delphi Panel was assembled. ResultsThe available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. ConclusionVaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.

Safety and effects of acetylated and butyrylated high amylose maize starch in recently diagnosed youths with type 1 diabetes; a Pilot Study.

Acetylated and butyrylated high amylose starch (HAMS-AB) is a prebiotic shown to be effective in type 1 diabetes (T1D) prevention in mouse models and is safe in adults with established T1D. HAMS-AB alters the gut microbiome profile with increased bacterial fermenters that produce short chain fatty acids (SCFAs) with anti-inflammatory and immune-modulatory effects. We performed a pilot study using a cross-over design to assess the safety and efficacy of 4 weeks of oral HAMS-AB consumption by recently diagnosed (< 2 years of diagnosis) youths with T1D. Seven individuals completed the study. The mean±SD age was 15.0±1.2 years, diabetes duration 19.5±6.3 months, 5/7 were female and 4/7 were White, all with a BMI of < 85th%. The prebiotic was safe. Following prebiotic intake, gut microbiome changes were seen, including a notable increase in the relative abundance of fermenters such as Bifidobacterium and Faecalibacterium. Treatment was also associated with changes in bacterial functional pathways associated with either improved energy metabolism (upregulation of tyrosine metabolism) or anti-inflammatory effects (reduced geraniol degradation). There were no differences in stool SCFA levels. Plasma metabolites associated with improved glycemia, such as hippurate, were significantly increased after treatment and there were positive and significant changes in the immune regulatory function of mucosal associated invariant T cells. There was a significant decrease in the area under the curve glucose but not C-peptide, as measured during a mixed meal tolerance testing, following the prebiotic consumption. In summary, the prebiotic HAMS-AB was safe in adolescents with T1D and showed promising effects on the gut microbiome composition, function and immune regulatory function.

Enhancing the efficacy of anti-PD-L1 therapy by cabozantinib in the treatment of advanced esophageal squamous cell carcinoma (ESCC): Rationales from a preclinical study.

e16036 Background: Anti-PD-1/PD-L1 therapy has changed the therapeutic landscape of ESCC. However, the efficacy of anti-PD-1 therapy alone remains modest. Cabozantinib, a multikinase inhibitor with immune modulatory effect in preclinical studies, in combination with atezolizumab has been investigated in various cancer types. We conducted a preclinical study to investigate the efficacy of cabozantinib plus anti-PD-L1 therapy using immunocompetent mouse ESCC models. Methods: From esophageal tumors developed in C57BL/6 mice following chronic exposure to 4-nitroquinoline 1-oxide, we generated several ESCC clones, which could be successfully propagated by in vitro culture for more than 25 passages. The viability of mouse ESCC clones in in vitro cell culture treated with various concentrations of cabozantinib (Adooq Bioscience LLC, Irvine, CA, US) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. We used a subcutaneous mouse model by implanting 5 x 106 murine ESCC cells (clone 104) in male 5-week-old C57BL/6 mice to evaluate the in vivo therapeutic efficacy of anti-PD-L1 therapy (10F.9G2 clone [a rat anti-mouse PD-L1 antibody], Bio X Cell, Lebanon, NH, US) by intraperitoneal (ip) injection, cabozantinib by oral gavage, or the combination of both agents. Tumor volumes were measured twice per week using bilateral calipers. Following two weeks of treatment and an additional week of observation, all mice were sacrificed for tumor harvest. Tumor weights were determined and compared among different treatment groups. Results: Cabozantinib, up to 30 μM, induced only mild growth suppression (13.8 to 26.6%) of 3 mouse ESCC cell clones (clones 001, 103, and 104) in vitro. In the sc tumor model implanted with mouse ESCC clone 104, the anti-PD-L1 monotherapy (10mg/kg, twice per week) did not affect the tumor growth ( P = 0.2000), suggesting that the sc tumor of clone 104 is an anti-PD-L1 primary resistant model. On the contrary, cabozantinib (10 to 30 mg/kg/day, 5 days per week, for 2 weeks) induced a dose-dependent inhibition of tumor growth (tumor weight decreasing from 22.7 to 84.4%) in the sc tumor model of clone 104. The combination of anti-PD-L1 plus cabozantinib induced a more significant suppression of tumor growth than either single treatment alone, and cabozantinib at the dose of 20 mg/kg exhibited more pronounced enhancing effect than at the dose of 10 mg/kg. Conclusions: This preclinical study demonstrated a synergistic antitumor effect of combining anti-PD-L1 therapy with cabozantinib in immunocompetent murine models of ESCC. A phase II trial is ongoing to investigate the efficacy of cabozantinib plus atezolizumab in advanced ESCC (NCT05007613) (This work was supported by NTUCCS-112-06, NSTC112-2314-B-002-150-, NSTC112-2314-B-002-268-, MOHW111-TDU-B-221-114006, and MOHW112-TDU-B-221-124006).

Biological Potential of a Bibenzyl Compound ‘Gigantol’ for the Treatment of Human Disorders: Pharmacological Activities and Analytical Aspects of an Active Phytochemical Isolated from Orchid

Background: Dendrobium chrysotoxum Lindl. is an important medicinal plant of the genus Dendrobium from the Orchidaceae family. Gigantol is one of the key bioactive phytochemicals found in Dendrobium plants. Gigantol is reported to have diverse pharmacological activities Aims: This narrative review explores the analytical aspects along with pharmacological activities of gigantol as reported in different scientific publications. Methods: To find appropriate information related to Dendrobium plants and gigantol, extensive data extraction was done using ScienceDirect, Google, PubMed, and Scopus databases, and diverse facts were collected, arranged and analyzed to know the therapeutic potential of gigantol. Analytical aspects of gigantol were also discussed in the present work. Results: Gigantol has a wide distribution in the Dendrobium officinale, Dendrobium chrysanthum, Dendrobium crystallinum, Dendrobium aphyllum, and Dendrobium devonianum. Available data indicates diverse pharmacological activities of gigantol. Preclinical studies have shown its effectiveness in the treatment of cataractogenesis, liver injury, leishmaniasis, nephrotoxicity, spasm, and skin disorders. Gigantol has been found to control hepatocellular cancer, lung cancer, breast cancer, bladder cancer, and cervical cancer. The neuroprotective, antinociceptive, anti-inflammatory, antioxidant, vasorelaxant, immune modulatory effect, antimalarial, and anti-herpetic properties of gigantol have also been observed. Applications of different analytical techniques for the isolation and characterization of gigantol were also discussed in detail. Conclusion: Gigantol has significant and diverse pharmacological activities that must be explored in clinical setup to develop therapeutic leads for different diseases and health conditions.

Experimental Animal Models in Obstetrics and Gynecology

This study focuses on two major diseases affecting women's reproductive health: endometriosis and polycystic ovary syndrome (PCOS). Endometriosis is characterized as an estrogen-dependent condition, highlighting estrogen's role in understanding the disease's development and treatment strategies. Rat and mouse models are crucial for comprehending the pathophysiology of endometriosis and testing new therapeutic approaches. These models are particularly valuable in evaluating the effects of hormones and immune system modulators on endometriosis. Conversely, experimental models of PCOS emphasize the central role of hyperandrogenism in the development of this condition. Models induced by substances like dehydroepiandrosterone, testosterone propionate, and letrozole provide insights into the metabolic and endocrinological disruptions associated with PCOS. The letrozole-induced model, in particular, helps in understanding the relationship between hormonal imbalances and the onset of PCOS. Experimental models of both diseases offer critical knowledge for both basic science research and clinical applications. They provide essential data for understanding the pathophysiology of these conditions and developing new treatment strategies. This study demonstrates how findings from experimental models can improve women's reproductive health and lead to more effective treatments for these diseases. An enhanced understanding of hormonal and immune system mechanisms will guide future research and offer innovative solutions for treating these conditions.

Efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine in elderly pre-treated patients with metastatic non-small-cell lung cancer.

e20556 Background: The subsequent therapy of elderly non-small cell lung cancer (NSCLC) without driver oncogene has always been a challenge due to the poor performance status and multiple comorbidities, especially in those who acquired resistance to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time which shows a better safety profile, antitumor angiogenesis, and immune modulatory effects compared with traditional chemotherapy. Here we designed an observational study to evaluate the efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine(mOV) in elderly pre-treated metastatic NSCLC. Methods: Patients aged 65 years and above who had been histologically or cytologically confirmed unresectable stage III and IV NSCLC were recruited for this study. All the pts had no EGFR mutation, ALK fusions, or ROS1 fusions and received at least one systematic treatment. Pts received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) for 6 cycles, followed by PD-1 inhibitors maintenance until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From May 2020 to June 2023, 23 pts were enrolled in the study. The median age was 70 with 18(78%) males. Median follow-up time was 22.8 months (range 3.9months-41.9months). The median PFS was 5.13 months (95%Cl: 3.1 months-7.1 months) and the median OS was 28.1 months (95%Cl: (15.2 months-NA). The ORR and DCR were 13% (95%C1: 1.44%-27.6%) and 69.6% (95%Cl: 49.2%-89.9%), respectively. The PFS (p = 0.459, HR = 0.671 95%CI 0.233-1.932) and OS (p = 0.483, HR = 1.607 95%CI 0.426-6.056) were similar between those pts who previously received immunotherapy (N = 16, 69.5%) and not. PD-L1 TPS didn’t affect the patient’s PFS (&lt;1% vs≥1%, p = 0.078, HR = 2.648 95%CI 0.895-7.835 ) and OS(&lt;1% vs≥1%, p = 0.306, HR = 2.202 95%CI 0.485-9.989). Adverse events (AEs) of any grade were observed in 20(86.9%) pts of which grade III-IV AEs occurred in 4 (17.4%) pts. These grade III-IV events consisted of interstitial pneumonia, pulmonary infection, leukopenia, and neutropenia. Immune-related adverse events (irAEs) occurred in 4 (17.4%) pts, of which grade III irAEs occurred in 2 (8.7%) patients with interstitial pneumonia. No grade 4 irAEs and grade 5 adverse events even occurred. Conclusions: The regimen of PD-1 inhibitors plus mOV for the subsequent therapy showed good overall survival benefits and safety in elderly patients with metastatic NSCLC without driver oncogene which suggests it is worth further exploration.

Alleviating lung injury and pulmonary fibrosis in radiotherapy-immunotherapy combination: The role of low-dose radiation therapy.

e14632 Background: Lung cancer continues to be the primary cause of cancer-related mortality on a global scale. The integration of radiotherapy and immunotherapy has yielded significant advancements in the treatment of locally advanced non-small cell lung cancer. However, the occurrence of treatment-associated pneumonia remains the predominant adverse event necessitating treatment cessation and permanent medication discontinuation. The immune-modulating effects of radiation therapy on the body contribute to a complex interplay between radiation and inflammation. Low-dose radiotherapy (LD-RT) has historically been utilized for the management of benign inflammatory conditions. Recently, LD-RT was found to be effective in treating severe pneumonia in patients with severe COVID-19 as well as acute respiratory distress syndrome (ARDS). This investigation seeks to examine the impact of LD-RT on lung tissue morphology and the inflammatory immune microenvironment in preclinical models of lung injury induced by high-dose radiotherapy combined with programmed death-1(PD-1) inhibitor therapy. Methods: 6-8 week old C57BL/6 mice were treated with a single high-dose thoracic radiotherapy (15Gy) and the PD-1 inhibitor (once a week), with or without the low-dose radiotherapy (1.0/1.5Gy) four weeks later. Lung tissue was collected one and a half months and three months respectively after the initial high-dose radiotherapy for evaluation using HE and Masson staining, Image J software for analysis of collagen volume fraction (CVF), and immunohistochemical staining for CD3+ and CD8+ T lymphocytes. Cytokine transforming growth factor (TGF)-β1、interleukin (IL)-6 and tumor necrosis factor (TNF)-α level in lung tissue was detected by ELISA. Statistical analysis was performed using GraphPad Prism 9.5.0 software. Results: The radiotherapy-immunotherapy combination (iRT) group exhibits notable lung injury characterized by the proliferation of alveolar type II epithelial cells, thickening of alveolar septa, interstitial edema, pulmonary congestion and bleeding, increased infiltration of inflammatory cells, and significant deposition of interstitial collagen fibers. In contrast, the iRT+ LD-RT group demonstrates a significant decrease in lung tissue damage, interstitial fibrosis, collagen volume fraction (CVF), levels of IL-6 and TGF-β, as well as the infiltration of CD3+ and CD8+T cells compared to the iRT group. Conclusions: Low-dose radiation has the potential to ameliorate lung injury induced by the combination of radiotherapy and PD-1 inhibitors by modulating the inflammatory milieu, thereby potentially mitigating the development of pulmonary fibrosis.

Early opioid exposure (EOE) and impaired efficacy in patients with advanced NSCLC treated with PD-L1 inhibition: A pooled post hoc analysis of the POPLAR and OAK trials.

2607 Background: Mechanistic evidence suggests opioid signaling to modulate anti-tumor immunity. Whether opioids exposure may affect outcome of patients (pts) treated with immune checkpoint inhibitors is unproven, with clinical evidence being flawed by the negative associative bias between pain and higher burden of disease. Methods: We conducted a post-hoc analysis of the phase 3 OAK (NCT02008227) and phase 2 POPLAR (NCT01903993) trials, which randomized (1:1) pts with advanced NSCLC to receive either atezolizumab or docetaxel. We assessed the differential impact of early opioids exposure (EOE), defined as a minimum of 7 days exposure to any systemic opioids in the time window ranging between -30 to +30 from treatment initiation on efficacy from immunotherapy vs chemotherapy. Pts with ≤30 days survival follow-up were excluded to avoid immortal time bias. Results: After the exclusion of 60 pts, 718 and 686 pts treated with atezolizumab and docetaxel were included, with 341 (47.5%) and 308 (44.9%) pts with EOE respectively (p=0.32) and a median follow-up of 25.5 months (95% CI: 22.8-25.9). Baseline characteristics was balanced across cohorts. In the pooled population, EOE was significantly associated with poorer ECOG-PS (p&lt;0.01) and burden of disease (p&lt;0.01). Univariable analysis showed EOE to be significantly associated with decreased objective response rate (ORR, 11.7% vs 19.8%, p&lt;0.01) and progression free survival (PFS, 1.9 vs 4.2 months, p&lt;0.01) in the atezolizumab cohort, whereas no effect on ORR (17.7% vs 14.4%, p=0.25) and a less pronounced effect on PFS (3.5 vs 4.1 months, p=0.02) was reported for the docetaxel cohort. The pooled multivariable backward stepwise Cox regression used to select variables for validating the results individuated ECOG-PS, histology, tumor burden and race. In multivariable models EOE was associated with decreased ORR (OR 0.58, 95%CI: 0.37-0.92), increased risk of progression (HR 1.47, 95%CI: 1.26-1.72) and death (HR 1.70, 95%CI: 1.42-2.03) in the atezolizumab cohort while no negative impact on ORR/PFS was confirmed among the docetaxel cohort, with a less strong effect on OS (HR 1.44, 95%CI: 1.21-1.72). Multivariable interaction tests confirmed the differential impact of EOE on ORR (p&lt;0.01) and PFS (p&lt;0.01) between treatment modalities (immunotherapy vs chemotherapy). The results were additionally confirmed using IPTW models including all the baseline variables with an optimal distribution (SMD &lt;0.05). Conclusions: EOE is associated with worse response/PFS from immunotherapy but not from chemotherapy exposure, suggesting a possible immune-modulating effect of opioids signaling on anti-tumor immunity. Considering that systemic opioids are the cornerstone of pain management in oncology further research for mitigation strategies, such as the potential use of PAMORAs, is needed. Clinical trial information: NCT02008227 and NCT01903993 .

Dopamine β-hydroxylase shapes intestinal inflammation through modulating T cell activation

BackgroundInflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined. MethodsCD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function. ResultsInhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells. ConclusionModulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.

Oral curcumin ameliorates acute murine campylobacteriosis

IntroductionHuman infections with the food-borne enteropathogen Campylobacter jejuni are responsible for increasing incidences of acute campylobacteriosis cases worldwide. Since antibiotic treatment is usually not indicated and the severity of the enteritis directly correlates with the risk of developing serious autoimmune disease later-on, novel antibiotics-independent intervention strategies with non-toxic compounds to ameliorate and even prevent campylobacteriosis are utmost wanted. Given its known pleiotropic health-promoting properties, curcumin constitutes such a promising candidate molecule. In our actual preclinical placebo-controlled intervention trial, we tested the anti-microbial and anti-inflammatory effects of oral curcumin pretreatment during acute experimental campylobacteriosis.MethodsTherefore, secondary abiotic IL-10-/- mice were challenged with synthetic curcumin via the drinking water starting a week prior oral C. jejuni infection. To assess anti-pathogenic, clinical, immune-modulatory, and functional effects of curcumin prophylaxis, gastrointestinal C. jejuni bacteria were cultured, clinical signs and colonic histopathological changes quantitated, pro-inflammatory immune cell responses determined by in situ immunohistochemistry and intestinal, extra-intestinal and systemic pro-inflammatory mediator measurements, and finally, intestinal epithelial barrier function tested by electrophysiological resistance analysis of colonic ex vivo biopsies in the Ussing chamber.Results and discussionWhereas placebo counterparts were suffering from severe enterocolitis characterized by wasting symptoms and bloody diarrhea on day 6 post-infection, curcumin pretreated mice, however, were clinically far less compromised and displayed less severe microscopic inflammatory sequelae such as histopathological changes and epithelial cell apoptosis in the colon. In addition, curcumin pretreatment could mitigate pro-inflammatory innate and adaptive immune responses in the intestinal tract and importantly, rescue colonic epithelial barrier integrity upon C. jejuni infection. Remarkably, the disease-mitigating effects of exogenous curcumin was also observed in organs beyond the infected intestines and strikingly, even systemically given basal hepatic, renal, and serum concentrations of pro-inflammatory mediators measured in curcumin pretreated mice on day 6 post-infection. In conclusion, the anti-Campylobacter and disease-mitigating including anti-inflammatory effects upon oral curcumin application observed here highlight the polyphenolic compound as a promising antibiotics-independent option for the prevention from severe acute campylobacteriosis and its potential post-infectious complications.

Ephedra sinica polysaccharide regulate the anti-inflammatory immunity of intestinal microecology and bacterial metabolites in rheumatoid arthritis

IntroductionEphedra sinica polysaccharide (ESP) exerts substantial therapeutic effects on rheumatoid arthritis (RA). However, the mechanism through which ESP intervenes in RA remains unclear. A close correlation has been observed between enzymes and derivatives in the gut microbiota and the inflammatory immune response in RA.MethodsA type II collagen-induced arthritis (CIA) mice model was treated with Ephedra sinica polysaccharide. The therapeutic effect of ESP on collagen-induced arthritis mice was evaluated. The anti-inflammatory and cartilage-protective effects of ESP were also evaluated. Additionally, metagenomic sequencing was performed to identify changes in carbohydrate-active enzymes and resistance genes in the gut microbiota of the ESP-treated CIA mice. Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry were performed to observe the levels of serum metabolites and short-chain fatty acids in the gut. Spearman’s correlational analysis revealed a correlation among the gut microbiota, antibiotic-resistance genes, and microbiota-derived metabolites.ResultsESP treatment significantly reduced inflammation levels and cartilage damage in the CIA mice. It also decreased the levels of pro-inflammatory cytokines interleukin (IL)-6, and IL-1-β and protected the intestinal mucosal epithelial barrier, inhibiting inflammatory cell infiltration and mucosal damage. Here, ESP reduced the TLR4, MyD88, and TRAF6 levels in the synovium, inhibited the p65 expression and pp65 phosphorylation in the NF-κB signaling pathway, and blocked histone deacetylase (HDAC1 and HDAC2) signals. ESP influenced the gut microbiota structure, microbial carbohydrate-active enzymes, and microbial resistance related to resistance genes. ESP increased the serum levels of L-tyrosine, sn-glycero-3-phosphocholine, octadecanoic acid, N-oleoyl taurine, and decreased N-palmitoyl taurine in the CIA mice.ConclusionESP exhibited an inhibitory effect on RA. Its action mechanism may be related to the ability of ESP to effectively reduce pro-inflammatory cytokines levels, protect the intestinal barrier, and regulate the interaction between mucosal immune systems and abnormal local microbiota. Accordingly, immune homeostasis was maintained and the inhibition of fibroblast-like synoviocyte (FLS) proliferation through the HDAC/TLR4/NF-κB pathway was mediated, thereby contributing to its anti-inflammatory and immune-modulating effects.

The Surgical Stress Response and Anesthesia: A Narrative Review.

The human physiological response "to stress" includes all metabolic and hormonal changes produced by a traumatic event at the micro or macro cellular levels. The main goal of the body's first response to trauma is to keep physiological homeostasis. The perioperative non-specific adaptation response can sometimes be detrimental and can produce systemic inflammatory response syndrome (SIRS), characterized by hypermetabolism and hyper catabolism. We performed a narrative review consisting of a description of the surgical stress response's categories of changes (neurohormonal and immunological response) followed by reviewing methods found in published studies to modulate the surgical stress response perioperatively. We described various preoperative measures cited in the literature as lowering the burden of surgical trauma. This article revises the anesthetic drugs and techniques that have an impact on the surgical stress response and proven immune-modulatory effects. We also tried to name present knowledge gaps requiring future research. Our review concludes that proper preoperative measures, adequate general anesthetics, multimodal analgesia, early postoperative mobilization, and early enteral nutrition can decrease the stress response to surgery and ease patient recovery. Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system and inflammatory system, with a consecutive impact on cancer recurrence and long-term outcomes.