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关键词： BV2 microglia cells   caspase-3 (CASP3)   influenza-associated encephalopathy (IAE)   TNF signaling pathway  

摘要： Although patients infected with the avian influenza H7N9 virus primarily present flu-like symptoms, recent clinical studies have found that viral encephalopathy caused by avian influenza H7N9 virus infection is an essential factor in patient deaths. In this study, the H7N9 virus was used to infect mouse microglia cells (MGs) BV2, central nervous system (CNS)-resident macrophages, to determine the infectivity of the H7N9 virus in MGs. Besides, we investigated immune reactions in H7N9 virus-infected mouse MGs by comprehensively analyzing the transcriptome and proteome. Results revealed that the H7N9 virus could infect BV2 cells, inducing cytopathic effects (CPEs) and producing infectious progeny virus. Furthermore, infection activated the tumor necrosis factor (TNF) signaling pathway and cleaved caspase-3, leading to cell death. These findings provide insights into the mechanisms by which the H7N9 virus causes lesions in the central nervous system.

关键词： CT-26 tumor   cytokines   natural killer cells   SAR-444245   T cells  

摘要： Anti-tumoral immunity requires coordination of diverse responses leading to durable tumor clearance. Immunotherapy leverages specific mechanisms of the immune system to improve effector cell-mediated attack of tumors. We engineered SAR-444245 [SAR'245, formerly known as THOR-707] as a not-alpha interleukin-2 (IL-2) designed for increased half-life and selective targeting of CD8+ T and natural killer (NK) cells while reducing targeting of immune-suppressive CD4+ regulatory T cells (Tregs). The anti-tumoral efficacy of SAR'245 was investigated using the syngeneic CT-26 mouse model characterized by high infiltration with Tregs and responsiveness to programmed cell-death protein-1 (PD-1) checkpoint inhibitory antibodies. We evaluated SAR'245 pharmacokinetics and peripheral and intra-tumoral pharmacodynamics employing cytometry, histochemistry, RNAseq and secreted cytokine readouts, and in vivo efficacy as single-agent and in combination with an anti-mouse PD-1 antibody. In CT-26 tumor-bearing mice, SAR'245 administration induced peripheral expansion of CD8+ T and NK cells, including T cell memory subpopulations, without significant Treg expansion. SAR'245 stimulated anti-tumor activity that was enhanced in combination with an anti-PD-1 checkpoint inhibitory antibody, promoting both long-term survival and rejection of tumor cells on re-challenge. This agent elevated lymphocytic infiltration of tumors and T cell clonal diversity, eliciting multiple intra-tumoral gene signatures reporting on enhanced effector cell activity and persistence in the tumor microenvironment. Overall, we demonstrate that the IL-2 not-alpha agent SAR'245 induces immune responses that promote infiltration of CD8+ T and NK cells with enhanced effector function, leading to durable antitumoral response. These findings suggest SAR'245 potential for the treatment of solid tumors, particularly in combination with inhibitors of PD-1.

关键词： TNF inhibitors   body composition   cytokines   inflammation   inflammatory activity   rheumatoid arthritis   sarcopenia  

摘要： Rheumatoid arthritis (RA) is a chronic inflammatory disease frequently associated with alterations in body composition, including reduced lean mass and increased fat mass. These alterations are thought to be driven by persistent systemic inflammation, which may be influenced by inflammatory activity and by therapeutic interventions. Objectives: This pilot study aimed to provide preliminary data on changes in body composition and inflammatory activity in biologic-naive patients with active RA during the initial 6 months of TNF inhibitor treatment, and to compare baseline body composition with healthy controls. We conducted a single-center, observational, 24-week pilot study of 70 biologic-naive RA patients with moderate-to-severe disease activity and 70 matched healthy controls. Lean mass, fat mass, and lean mass index (LMI) were measured using dual-energy X-ray absorptiometry at baseline for both groups, and after 6 months only in the RA group. Clinical, laboratory, adipokines, and cytokine parameters were also recorded. At baseline, RA patients had lower lean mass and LMI than controls. Over 6 months, RA patients showed significant clinical and laboratory improvement, with a corresponding increase in lean mass and LMI. No statistically significant change was observed in fat mass. The increase in lean mass was paralleled by a reduction in inflammatory markers. The LMI was inversely associated with female sex (β = -0.562) and C-reactive protein (β = -0.432) and directly associated with body mass index (β = 0.570). Similar associations were observed for total lean mass and change in lean mass, as well as for DAS28 (β = -0.333). This pilot study provides preliminary evidence that TNF inhibitor therapy may be associated with increased lean mass and decreased inflammation in RA patients. Owing to the absence of a comparator RA group not receiving TNF inhibitors, these findings should be interpreted as hypothesis-generating.

关键词： 多种细胞因子   急性胰腺炎   继发感染   诊断价值  

摘要： 探讨IL-6、TNF-α、IL-8、PCT及CRP在急性胰腺炎继发感染中的诊断效能,并分析其与临床结局之间的联系。方法 纳入2024年2月至2025年2月期间收治的50例急性胰腺炎患者,分为实验组和对照组,各25例。采集外周血清样本,利用酶联免疫吸附法测定IL-6、TNF-α、IL-8、PCT与CRP水平。运用ROC曲线评估各指标的诊断准确性。对两组住院时间和抗生素使用时长进行对比分析,以揭示炎性因子水平变化与临床恢复之间的潜在关系。结果 实验组IL-6、TNF-α及PCT水平均显著升高,差异具有统计学意义。IL-6平均浓度为135.2±28.4pg/mL,对照组为62.3±15.1pg/mL。TNF-α分别为45.6±9.8与18.7±4.2pg/mL。PCT水平则为2.1±0.6ng/mL对比0.3±0.1ng/mL。ROC分析显示,PCT单独诊断价值最强(AUC=0.93),多指标联合检测诊断效能更高(AUC=0.96)。值得注意的是,对照组住院时长为14.2±3.1天,而实验组仅为9.8±2.5天。抗生素使用天数缩短,死亡率随之降低。结论 IL-6、TNF-α及PCT在急性胰腺炎继发感染中表现出较高的敏感性与特异性。PCT作为单一指标,其诊断效力最为突出。多因子联合检测提供更具参考价值的判断依据。炎症因子的动态变化与治疗反应密切相关,提前干预或可缩短住院周期,优化抗菌治疗路径。未来可尝试构建基于这些生物标志物的风险评分模型,用以早期识别感染倾向,辅助临床决策。

关键词： HEK-Blue cell-based assays   IL-15   Immunotherapy   TGF-β receptor II   anti-drug antibodies   immunogenicity   neutralization  

摘要： To comply with regulatory guidelines and ensure that biopharmaceutical agents meet safety and efficacy, we developed an analytical method to detect anti-drug antibodies (ADAs) generated in response to HCW9218, a fusion molecule containing the human soluble TGF-β RII and IL-15/IL-15 Rα sushi domains. The method demonstrated a sensitivity of 34.6 ng/mL with a suitably high degree of specificity, selectivity, and precision. To assess the neutralizing capacity of ADAs, we developed cell-based assays specific to IL-15 and TGF-β RII. These assays effectively discriminated the neutralizing activity of sera spiked with neutralizing antibody (NAb). The determination of positive NAb was based on absorbances corresponding to a threshold value of 30% inhibition of IL-15 or TGF-β RII activity. Each assay was validated using human sera from ongoing clinical trials. ADAs were detected in most sera tested with titers less than 10,000. None of the sera inhibited IL-15 and TGF-β RII activity by more than 30%. Interestingly, circulating TGF-β present in sera mimicked the action of NAb by binding to soluble TGF-β RII resulting in higher baseline neutralization activity. These methods proved to be suitable for detection of ADAs and NAbs in HCW9218 clinical samples or analogs sharing similar receptor/cytokine subunits and/or downstream signaling pathways.

关键词： Immune-mediated gastrointestinal (GI) disorders   Achalasia   Autoimmune Gastritis (AIG)   Celiac Disease (CeD)   Inflammatory Bowel Disease (IBD)   Autoimmune Enteropathy (AIE)   Gastrointestinal (GI) vasculitis   Eosinophilic GI disorders (EGIDs)   GI Sarcoidosis   AMPs   Antimicrobial Peptides   ANCA   Anti-Neutrophil Cytoplasmic Antibodies   ASCA   Anti-Saccharomyces cerevisiae Antibodies   AT   Autoantibodies   AIE   Autoimmune Enteropathy   AIG   Autoimmune Gastritis   CeD   Celiac Disease   CC   Collagenous Colitis   CRC   Colorectal Cancer   CD   Crohn’s Disease   CTLA-4   Cytotoxic T-Lymphocyte Associated Protein 4   ECM   Extracellular matrix   DAMPs   Damage-Associated Molecular Patterns   EGDs   Eosinophilic Gastrointestinal Disorders   EGPA   Eosinophilic Granulomatosis with Polyangiitis   EoE   Eosinophilic Esophagitis   EoG   Eosinophilic Gastritis   EoN   eosinophilic enteritis   EoC   Eosinophilic Colitis   FC   Fecal Calprotectin   FOXP3   Forkhead Box P3   Gd-IgA1   Galactose-deficient IgA1   GPA   Granulomatosis with Polyangiitis   HLA   Human Leukocyte Antigen   HSCT   Hematopoietic Stem Cell Transplantation   IL   Interleukin   IPEX   Immune dysregulation   Polyendocrinopathy   Enteropathy   X-linked Syndrome   JAK   Janus Kinase   LC   Lymphocytic Colitis   LHM   Laparoscopic Heller Myotomy   MICA   MHC Class I Chain-related Protein A   MC   Microscopic Colitis   MPO   Myeloperoxidase   MSCs   Mesenchymal Stem Cells   NSAIDs   Non-Steroidal Anti-Inflammatory Drugs   PCD   Primary Ciliary Dyskinesia   POEM   Peroral Endoscopic Myotomy   pMHC   Peptide-Major Histocompatibility Complex   PMN   Polymorphonuclear Cells   PR3-ANCA   Proteinase 3 Anti-Neutrophil Cytoplasmic Antibodies   PPI   Proton Pump Inhibitors   PTX3   Pentraxin 3   PTH   Parathyroid Hormone   RBC   Red Blood Cell   SNPs   Single Nucleotide Polymorphisms   SFCAs   Short-Chain Fatty Acids   STAT3   Signal Transducer and Activator of Transcription 3   Tfh: T Follicular Helper cells TGF-β   Transforming Growth Factor Beta   Th   T helper Cells   TLR   Toll-Like Receptor   TGF   Transforming Growth Factor   TNF-α   Tumor Necrosis Factor alpha   Tregs: Regulatory T Cells   TRM   Tissue-Resident Memory   TR1   T regulatory Type-1   UC   Ulcerative Colitis   VZV   Varicella-Z  

摘要： This review examines recent developments in immune-mediated gastrointestinal (GI) disorders, focusing on the immunopathogenesis and evolving therapeutic landscapes of conditions such as Autoimmune Enteropathy (AIE), Autoimmune Gastritis (AIG), Achalasia, Celiac Disease (CeD), Inflammatory Bowel Disease (IBD), GI Sarcoidosis, GI vasculitis and Eosinophilic GI disorders (EGIDs), among others. We explore new insights into the mechanisms underpinning the dysregulated immune responses that fuel these disorders, influenced by genetic factors and environmental insults, including dysbiosis. The review highlights the roles of key immune components, fibrosis and gut microbial changes in disease pathogenesis, as identified using immunological, histopathological, omics and microbiome studies, and discusses novel therapeutic strategies potentially capable of improving patient outcomes. Despite significant progress, several challenges in the effective management of these conditions remain, underscoring the need for continued research to develop targeted, disease-modifying therapies that do not compromise normal immunity.

关键词： nanoparticles   Saussurea costus   NF-kappa B   TNF-alpha   inflammation  

摘要： Objectives Porphyromonas gingivalis is a major contributing pathogen in periodontitis and triggers an inflammatory response that leads to tissue damage, primarily through the activation of proinflammatory cytokines such as nuclear factor kappa B (NF-kappa B) and tumor necrosis factor-alpha (TNF-alpha). Saussurea costus , a medicinal plant known for its anti-inflammatory properties, offers a potential alternative to prevent inflammation. This study explores the effects of S. costus nanoparticles on inflammation in periodontitis, specifically examining their ability to reduce the expression of NF-kappa B and TNF-alpha. Materials and Methods Twenty male Wistar rats were injected with P. gingivalis into the central incisor region of the mandible to induce periodontitis. The rats were then treated with S. costus nanoparticles, alongside a control group. Immunohistochemical staining was performed to assess the expression of NF-kappa B and TNF-alpha at two time points: 2 and 5 days posttreatment. Bone and lower anterior gingival sulcus tissues were analyzed for immunohistochemical expression of these markers. Statistical Analysis Statistical analysis was performed using the Kruskal-Wallis and Mann-Whitney U tests. Results Treatment with S. costus nanoparticles resulted in significantly lower expressions of NF-kappa B and TNF-alpha compared with the control group at both 2 and 5 days posttreatment ( p < 0.05). Conclusion The S. costus nanoparticles effectively reduced NF-kappa B and TNF-alpha expression in periodontitis, with a more pronounced effect observed on day 5 compared with day 2, suggesting its potential as a therapeutic agent in managing periodontal inflammation.

关键词： acute lung injury   lung delivery   nanomedicine   siRNA   TNF-alpha  

摘要： This study investigates the potential of pulmonary delivery of siRNA as an emergency therapy for acute lung injury (ALI). To obtain a quick anti-inflammatory response, TNF-alpha, a critical pro-inflammatory cytokine, is knocked down for its early involvement in inflammatory responses. Therefore, TNF-alpha siRNA-lipid nanoparticles (LNPs) are designed and characterized for cellular uptake in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophages, primary alveolar macrophages, and neutrophils from a murine ALI model. Intracellular trafficking and siRNA cytoplasmic release are evaluated in untreated and LPS-activated RAW264.7 cells. LPS-activated cells exhibit a fast and strong uptake of LNPs, including in primary cells. In RAW264.7 cells, significant endosomal escape and siRNA cytoplasmic release are observed after 16 h. In vitro efficacy studies reveal consistent TNF-alpha inhibition across pre-, co-, and post-incubation protocols, confirming the versatility of siRNA-LNPs in preventive or curative conditions. After intratracheal administration of TNF-alpha siRNA-LNPs in a murine ALI model, the distribution of LNPs demonstrates an accumulation in immune cells, including macrophages and neutrophils, reducing TNF-alpha and IL-6 levels, indicating a rapid anti-inflammatory effect. This work underscores the efficacy of TNF-alpha siRNA-LNPs in treating lung inflammatory diseases like ALI and highlights the importance of optimizing LNP distribution and delivery timing to enhance therapeutic outcomes.

关键词： genomics   GWAS   HLA   phenome-wide   biobank   summary statistics   UKBB   FinnGen  

摘要： The human leukocyte antigen (HLA) region plays an important role in human health through its involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome wide for 412,181 Finnish individuals and 2,459 diseases. Across the 1,035 diseases with a genome-wide association study association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 diseases, including 1,750 associations uncovered by haplotype analysis. We found that some haplotypes show both risk-increasing and protective associations across different diseases, while others consistently increase risk across diseases, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk and underscores the importance of classical and non-classical genes as well as non-coding variation.

关键词： 预后   T细胞免疫功能   生存率   口腔癌   PD1免疫治疗  

摘要： 对口腔癌患者采取PD1免疫疗法的效果展开评价,并分析T细胞免疫功能受到的影响。方法 从2022.4至2024.4抽选50例口腔癌患者实施数字表分组,一组病例25。对比组:常规化疗,讨论组:基于常规化疗行PD1免疫治疗,观察症状评分、T细胞免疫功能、病情缓解率及预后。结果 治疗后,口干、吞咽困难、头痛、疲劳、口腔黏膜炎症状评分比较P<0.05,讨论组低于对比组,有意义。T细胞免疫功能检测比较P<0.05,讨论组在改善免疫功能方面比对比组更占优势,有意义。病情缓解率比较P<0.05,讨论组高于对比组,有意义。预后比较P<0.05,讨论组随访3月、6月、12月的总死亡率低于对比组,有意义。结论 常规化疗治疗口腔癌时配合PD1免疫疗法可以促使症状快速改善,改善T细胞免疫功能,病情缓解有效率高,预后较佳,具有推广价值。