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关键词： influenza virus   innate   smoking   IFN-gamma   inflammation  

摘要： Background Cigarette smoke (CS) exposure increases the frequency and severity of respiratory influenza A virus (IAV) infections in humans and increases mortality in mice. There is evidence that Cytochrome P450 family 1 subfamily B member 1 (CYP1B1) enhances lung injury during hyperoxic exposure in animal models. We used an in-vivo mouse model to assess the hypothesis that CYP1B1 modifies innate immune responses to CS and alters survival during IAV *** We measured CYP1B1 induction in bronchial epithelial cells in smokers and nonsmokers obtained by bronchoscopy by whole transcriptome analysis. To determine whether CYP1B1 knockout (CYP KO) improves mortality and reduces lung injury in CS-exposed mice, we compared the survival rates, host immune responses, and lung-to-body weight ratio of CYP KO mice with the wild-type (WT) mice following challenge with IAV with or without CS *** CYP1B1 is one of the most highly upregulated genes in human lung epithelia derived from cigarette smokers. In CS-exposed mice, CYP1B1 knockout (CYP KO) significantly increased survival during IAV infection. In both nonsmoking (NS) and CS mice, CYP KO significantly enhanced IAV-induced increases in total immune cell numbers in bronchoalveolar lavage fluid (BALF) without causing additional lung injury. CYP KO caused a more rapid IFN-gamma response to IAV infection in lungs from both NS- and CS-exposed mice. Specifically, we found that IFN-gamma was significantly increased in BALF and in the lung at day 5 post-infection (p.i.) in these mice. Flow cytometry showed that innate lymphocytes produced early IFN-gamma in the lungs of KO mice. We confirmed the importance of IFN-gamma for CYP KO survival by adding IFN-gamma antibody to IAV-infected CYP KO mice. IFN-gamma antibody treatment of CS-exposed CYP KO mice completely abolished the improved survival rate seen in KO mice without IFN-gamma antibody treatment. However, IFN-gamma administration to CS-exposed WT mice did not i

关键词： anti-drug antibodies   anti-TNF therapy   immunogenicity   rheumatoid arthritis   CD4 T cells  

摘要： Treatment efficacy of patients receiving anti-TNF antibodies is limited by the formation of anti-drug antibodies. These are observed in most adalimumab-treated rheumatoid arthritis patients, despite the adjuvant-free and human sequence-derived nature of the antibody. The class switched phenotype and high affinity of these antibodies suggest CD4 T-cell involvement in their formation. In this study, we investigated the potential epitopes in the functional domain of adalimumab and assessed their actual HLA II presentation and induction of CD4 T-cell responses in exposed patients. The binding strength of overlapping adalimumab-derived peptides to 27 DR and 14 DQ HLA alleles was predicted in silico. 10 strong and 44 medium-binding 10-mer peptides were identified within the variable regions of the heavy and light chain of adalimumab. HLA-DR-mediated antigen presentation of selected peptides by monocyte-derived dendritic cells was determined by mass spectrometry of the peptide pool eluted from isolated HLA-DR complexes. Binding of the variable region peptides of heavy (H41-62) and light chains (L18-39) was demonstrated. The presence of adalimumab-specific CD4 T-cells in adalimumab-experienced patients was investigated via peptide stimulation of peripheral blood mononuclear cells and assessment of T-cell proliferation. Anti-adalimumab CD4 T-cell responses were observed against four variable region peptides in a group of adalimumab-experienced RA patients. Some of these responses were also present in healthy control donors. This study identifies immunologically relevant CD4 T-cell epitopes in the variable region of the human therapeutic antibody adalimumab based on RA patients' reactivity. Modification of these epitopes or concomitant therapy that targets or prevents adalimumab-specific T cell responses could be beneficial for patients with significant anti-drug responses.

关键词： Cytokine   engineering   IL-7   immunotherapy  

摘要： BackgroundIL-7 is a cytokine that plays a critical role in the development and proliferation of many different immune cells. IL-7 is notably important for the proper development and activity of T cells and B cells. Additionally, the cytokine plays a role in the function of natural killer cells and dendritic cells. Because of this innate biological activity, IL-7 has gained traction as a potential immunotherapy for multiple *** conducted a comprehensive literature review to explore the physiological role of IL-7 and current applications harnessing the biology of IL-7 as a therapeutic. We also investigated the ways in which IL-7 is being engineered to enhance its therapeutic ***, IL-7 has demonstrated efficacy in adoptive cell therapy models and as a vaccine adjuvant. The cytokine has also been used as a treatment for sepsis and other chronic infections. To further enhance its therapeutic efficacy, IL-7 has been engineered by fusing the cytokine to antibody fragments or other bioactive or targeting molecules. These engineered IL-7 therapeutics seek to improve the cytokine's pharmacokinetic and immunological properties and reduce off-target ***-7 immunotherapies largely remain at the preclinical stage, but there is growing interest in IL-7's many therapeutic applications and increasing opportunities to further engineer the molecule for future clinical translation.

关键词： Cell interactions   Stromal cells   IFN gamma   Inflammation  

摘要： Background Pigmented villonodular synovitis (PVNS) is a rare articular disease characterized by aggressive synovial proliferation, with localized or diffuse forms. PVNS shares features of an inflammatory disease such as rheumatoid arthritis (RA), including immune cell infiltrate. Thus, we aimed to evaluate PVNS synoviocyte response to inflammatory stimulation or cell interactions to better understand their role in pathophysiology. Results were compared with those in RA. Methods Synoviocytes were treated with pro-inflammatory cytokines, IL-17 and/or TNF. IL-6 and IL-8 production was evaluated by ELISA in culture supernatants after 48 h. Migratory capacity was evaluated by a cell scraping assay. Peripheral blood mononuclear cells (PBMC) from healthy donors were co-cultured with PVNS or RA synoviocytes during 48 h, in the presence or not of phytohemagglutinin (PHA). Cytokine production (IL-17, IL-6, IFN-gamma, IL-10, IL-1 beta and TNF) was measured by ELISA. Results The addition of IL-17 and TNF stimulated IL-6 and IL-8 secretion by both PVNS and RA synoviocytes, with similar responses between PVNS and RA synoviocytes. The highest production of IL-6 and IL-8 was obtained with the combination of IL-17 + TNF. Diffuse PVNS synoviocytes were less potent to cover a scratch area than localized PVNS or RA synoviocytes (p < 0.05). Finally, responses to cell interactions were assessed using co-cultures between synoviocytes and activated immune cells. IL-17, IL-6, IFN gamma, IL-10, IL-1 beta and TNF production was measured after 48 h. Cell interactions induced massive cytokine production, mainly in PHA activated condition. The source of stromal cells affected the secretion resulting from these interactions. Localized and diffuse PVNS synoviocytes induced more IL-17 than RA synoviocytes (p <= 0.01). Localized PVNS induced more IFN gamma than both diffuse PVNS and RA synoviocytes (p <= 0.05). IL-10 production was negatively correlated with IFN gamma secretion. Conclusion In conclu

关键词： Interleukin-2 (IL-2)   Interleukin-2 receptor (IL-2R)   T cell growth factor   Regulatory T cells (Tregs)   autoimmunity   cancerimmunology   transplantation  

摘要： BackgroundThe discovery of interleukin-2 (IL-2) and its receptor (IL-2R) almost 50 years ago revolutionized immunology, marking a pivotal moment in understanding T cell biology and immune regulation. Initially identified as a T cell growth factor, IL-2 unveiled critical insights into cytokine-mediated immune cell proliferation and *** review highlighted the characterization of IL-2R as a multi-chain receptor complex set a precedent for decoding cytokine receptor signaling. The unique interplay between IL-2 and its high-affinity receptor component, IL-2R alpha, epitomizes the principle of specificity and efficiency in cytokine signaling, enabling precise immune modulation. Regulatory T cells (Tregs) exploit IL-2R alpha high affinity to outcompete effector T cells for IL-2, ensuring immune tolerance and preventing *** its foundational role in immune homeostasis, leveraging IL-2 for therapeutic purposes has proven ***-2-based therapies hold transformative potential in autoimmunity, cancer immunology, and transplantation, yet they remain elusive due to the complex balance between immunostimulatory and immunosuppressive effects. This review explores the milestones in IL-2 biology, its dualistic functions, and the ongoing quest to harness its therapeutic promise.

关键词： 薯蓣皂苷   类风湿关节炎   胶原诱导关节炎   IL-17   γδT细胞   Vδ4  

摘要： 目的探究薯蓣皂苷调控IL-17+γδT细胞治疗关节炎的作用机制。方法牛Ⅱ型胶原诱导DBA/1小鼠建立胶原诱导关节炎（collagen induced arthritis，CIA）模型，随机分为CIA模型组、甲氨蝶呤（methotrexate，MTX）阳性对照组，以及薯蓣皂苷低（Dioscin-L）、中（Dioscin-M）、高（Dioscin-H）给药组。干预后，苏木精-伊红（H&E）染色分析关节病理损伤；ELISA法检测抗胶原特异性抗体和致炎因子IL-17水平；流式细胞术检测γδT细胞及亚型表达，以及IL-17分泌水平。结果薯蓣皂苷明显降低CIA小鼠关节炎严重程度评分，改善关节病理损伤，抑制脾淋巴细胞产生IL-17及抗胶原特异性抗体总IgG、IgG3的水平，抑制淋巴结γδT细胞、脾脏γδT细胞和亚型Vδ4细胞产生比例。干预组淋巴结Vδ4细胞产生IL-17的水平低于模型组，但差异无显著性。结论薯蓣皂苷对CIA具有明显的治疗效应，其作用机制可能与抑制γδT细胞有关，而与γδT细胞来源的IL-17无关。

关键词： community-dwelling elderly   methylation   sarcopenic obesity   TNF-alpha   TWEAK/Fn14  

摘要： Sarcopenic obesity is a primary factor contributing to the decline in the quality of life among the elderly in our country. Studies have shown that hypomethylation of tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) is associated with sarcopenia. Our research primarily explores whether this mechanism also affects the progression of sarcopenic obesity. A total of 120 subjects were grouped into the case (sarcopenic obesity) and control (non-sarcopenic and nonobese) groups, with 60 subjects in each group based on power test (medium effect size, power = 80%). Bisulfite sequencing was used to assess the methylation status of TWEAK/Fn14 in these subjects. ELISA was employed to measure the plasma concentrations of TWEAK, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-4, IL-6, and IL-10. SPSS 17.0 and R software was used for statistical analysis, employing multiple logistic regression to adjust for residual confounding factors, and Student t tests for difference analysis. Compared to the case group, the control group had higher methylation levels at CpG20, CpG30 sites in TWEAK (P = .043 for both). Additionally, the control group showed higher methylation level at CpG25 site in Fn14 (P = .025). After adjusting for hypertension, diabetes, triglyceride levels, gender, and age, Student t tests covariance confirmed significant differences in the enrichment levels of TWEAK, TNF-alpha, IL-10, and IL-4 of patients in case group (P-TWEAK = .017, PTNF-alpha < .001, PIL-10 = .010, PIL-4 = .016). Multivariate logistic regression analysis revealed that higher plasma levels of TWEAK and TNF-alpha were significantly associated with the incidence of sarcopenic obesity (odds ratios = 1.024, 95% confidence interval = 1.006-1.042;odds ratios = 2.537, 95% confidence interval = 1.697-3.793). This evidence suggested that hypomethylation of TWEAK/Fn14 also affected sarcopenic obesity progression. Increased enrichment of TWEAK a

关键词： Ankylosing spondylitis   TNF inhibitors   IL-17 inhibitors   Biologics   Second or higher line   Drug retention   Real-world data  

摘要： BackgroundFor patients with ankylosing spondylitis (AS) who experience inefficacy or adverse events with biologics, no recommendations exist regarding the preference for class cycling or switching as a second- or higher-line biologics. Previous studies on the drug retention of TNF and IL-17 inhibitors in AS patients with prior biologics exposure have limitations, including relatively short follow-up periods, exclusion of patients with extra-articular manifestations, and a primary focus on second-line treatment. This study aimed to compare the retention rates of TNF and IL-17 inhibitors in AS patients with prior biologics experience, over a relatively longer follow-up period in real clinical *** total of 148 AS cases receiving either a TNF or IL-17 inhibitor as a second- or higher-line biologic were retrospectively analyzed after propensity score matching. Patient characteristics at the time of cycling or switching and drug retention were compared between the two groups. Subgroup analyses were conducted based on the reasons for drug discontinuation. Cox regression analyses were used to identify the factors associated with drug *** median follow-up period was 31.4 months, and drug survival tended to be lower for IL-17 inhibitors than for TNF inhibitors in the Kaplan-Meier analysis (P = 0.134). The lower retention of IL-17 inhibitors was more pronounced when discontinuations unrelated to treatment failure were censored (P = 0.034) or when used for reasons other than psoriasis aggravation (P = 0.028). However, in multivariable Cox regression, the number of previous biologics (HR: 1.62, 95% CI: 1.17-2.23, P = 0.003) and BASDAI (HR: 1.3, 95% CI: 1.03-1.65, P = 0.030) were significantly associated with drug discontinuation, whereas the class of biologics did not reach statistical significance (HR: 2.11, 95% CI: 0.96-4.63, P = 0.064).ConclusionIn patients with AS who had prior experience with biologics, the drug retention of TNF inhibito

关键词： cisplatin   nephrotoxicity   caspase-3   Nrf2   oxidative stress   STAT3 cisplatin   stat3  

摘要： Introduction Cisplatin (CIS) is a productive chemotherapeutic agent that is effective against a variety of cancer types. Its utilization is linked to acute kidney injury and other adverse consequences. Among its toxic effects are oxidative stress, apoptosis as well as inflammation. Saudi Tamarix honey (STH) is a valuable product with plentiful nutritional and health benefits, demonstrating advantageous effects against inflammation and oxidative stress. Therefore, this study examined the potential of STH to prevent oxidative stress, apoptosis, inflammation, and kidney impairment that are induced by CIS in rats, pointing to the entanglement of the Nrf2, the caspase-3, and the IL-6/STAT3/TNF-alpha signaling *** Histopathological examinations of the kidney were also used to evaluate cisplatin-induced nephrotoxicity. The rats received STH (50, 100 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day *** CIS caused injury to the glomeruli and the tubules, increased lipid peroxidation, TNF-alpha, IL-6, cleaved caspase-3, and decreased cellular antioxidants in the kidneys of rats. STH effectively prevented tissue injury, and ameliorated oxidative stress, inflammatory markers, in addition to caspase-3 in CIS-administered rats. STH is rich with antioxidants, suppressed STAT3 protein expression, and upregulated Nrf2 in CIS-administered rats. In conclusion, STH mitigated CIS-induced kidney injury by reducing oxidative stress, suppressing STAT3 and caspase-3, inhibiting pro-inflammatory mediators, and enhancing Nrf2 signaling. On the other hand, metabolomic profiling proposed the presence of 15 metabolites belonging to the chemical classes, phenolic acids, flavonoids and sterols, where phenolic acids were the most abundant classes.