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关键词： IL-6   Cardiac fibroblasts   Purinergic signalling   Myocardial infarction   Adenosine  

摘要： Elevated interleukin-6 (IL-6) levels are linked to an increased risk of cardiovascular mortality in myocardial infarction (MI). Targeting IL-6 and its downstream signalling pathways represents a therapeutic strategy;however, its cellular sources and regulatory mechanisms of IL-6 remain incompletely understood. In this study, Alter and colleagues investigated the primary cell type that produces IL-6 in post-MI murine heart and the role of purinergic signalling in regulating IL-6 formation. Using cellular and mouse models, the authors identified cardiac fibroblasts as the predominant source of IL-6. Further analysis revealed that the IL-6 formation in cardiac fibroblasts is regulated by adenosine A2B receptors. Of further importance, they elucidated that T cells highly express CD73, leading to significant adenosine formation, which in turn enhances IL-6 production via Gq activation in cardiac fibroblasts following MI. These findings reveal a dynamic interplay between immune cells and fibroblasts in shaping the post-MI inflammatory response. This study suggests the adenosine-A2B receptor-IL6 axis as a potential therapeutic target to mitigate inflammation and improve cardiomyocytes salvage in MI.

关键词： Myoblasts   Inflammation   Skeletal muscles   Analysis of variance   MTT assay   Cytokine therapy   Cytokines   Enzyme-linked immunoassays  

摘要： Muscle inflammation is one of the hallmarks of Duchenne muscular dystrophy (DMD). Dystrophin-deficient skeletal muscle cells produce higher levels of pro-inflammatory cytokines such as interleukin 1 beta (IL-1 beta) in response to toll-like receptor stimulation compared to normal muscle skeletal cells. IL- 1 beta induces the human skeletal muscle secretion of the myokine Interleukin-6 (IL-6). Here, we evaluated the effect of a human IgG1 kappa monoclonal antibody (canakinumab (Ilaris (R))) that specifically blocks the IL-1 beta effect on IL-6 secretion by human skeletal muscle cells. Canakinumab is an excellent candidate for therapeutic repositioning to treat DMD because it is an FDA-approved drug to treat periodic fever syndromes and systemic juvenile idiopathic arthritis. Unlike previous generations of IL-1 inhibitors, canakinumab is highly specific for the IL-1 beta ligand, has a longer half-life, and does not interfere with other IL-1-activated inflammatory pathways. Following cell culture optimization and viability assays to assess toxicity, skeletal muscle cells were stimulated with IL-1 beta (10 ng/mL) for 48 hours in the presence of nine concentrations of canakinumab ranging from 0.001 nM to 1000 nM, and IL-6 production was measured with an enzyme-linked immunosorbent assay. Pre-incubation of myoblasts with canakinumab before IL-1 beta-stimulation, significantly reduced IL-6 production at concentrations of 1, 10, 100, 250, and 1000 nM relative to controls, yielding an IC50 of 0.264 nM. On the other hand, co-incubation of canakinumab with IL-1 beta before addition to myoblasts resulted in a significant inhibition with the IC50 reducing to 0.126 nM, less than half of the previous method. Canakinumab also did not affect myotube viability at 10 nM and was also able to significantly reduce the production of IL-6, when the cells were stimulated with IL-1 beta (10 ng/ml). Taken together, our results show that canakinumab is a potent inhibitor of IL-1 beta signaling

关键词： cytokines   uveitis   multiple-sclerosis   EAU   EAE   JAK/STAT   exosomes   nanobody  

摘要： Cytokines influence cell-fate decisions of na & iuml;ve lymphocytes and determine outcome of immune responses by transducing signals that regulate the initiation, intensity and duration of immune responses. However, aberrant regulation of physiological levels of cytokines contribute to the development of autoimmune and other inflammatory diseases. The Interleukin 6 (IL-6)/IL-12 superfamily of cytokines have a profound influence on all aspects of host immunity and our focus in this review is on the signaling pathways that mediate their functions, with emphasis on how this enigmatic family of cytokines promote or suppress inflammation depending on the physiological context. We also describe regulatory lymphocyte populations that suppress neuroinflammatory diseases by producing cytokines, such as IL-27 (i27-Breg) or IL-35 (i35-Breg and iTR35). We conclude with emerging immunotherapies like STAT-specific Nanobodies, Exosomes and Breg therapy that ameliorate CNS autoimmune diseases in preclinical studies.

关键词： Intervertebral disc degeneration   M Phi   Polarization regulation   Nanoparticles   Cellulose hydrogel  

摘要： Intervertebral disc degeneration (IDD) is a degenerative spinal condition characterized by disc structural damage, narrowing of joint spaces, and nerve root compression, significantly reducing patients' quality of life. To address this challenge, a novel therapeutic strategy was developed using cellulose supramolecular hydrogel as a carrier to deliver IL4I1-modified M Phi membrane biomimetic nanoparticles (CHG@IL4I1-MNPs) to target tissues. This hydrogel exhibits excellent biocompatibility and mechanical properties while enabling sustained drug release in the degenerative disc microenvironment, enhancing therapeutic outcomes. CHG@IL4I1-MNPs effectively regulate M Phi polarization by promoting M2 M Phi activation, thereby improving immune microenvironment balance. Animal studies demonstrated that CHG@IL4I1-MNPs alleviated symptoms of IDD, reduced inflammation, and supported tissue repair, highlighting its potential to reduce reliance on long-term medication and improve quality of life. The strategy uniquely combines nanoparticle technology with immunomodulation, achieving precise targeting of M Phi s. Beyond IDD, this approach offers potential applications in other immune-related diseases, providing a versatile platform for nanomedicine. This study introduces an innovative method to treat IDD and advances the integration of immunotherapy and nanotechnology, offering both clinical benefits and new directions for future research. These findings hold strong potential for improving patient outcomes and expanding treatment options for related diseases.

关键词： interleukin-10   interleukin-18   meta-analysis   nasopharyngeal carcinoma   polymorphism  

摘要： Objective To evaluate the possible association of the cytokine polymorphisms with the risk of nasopharyngeal carcinoma (NPC). Methods We performed a comprehensive search of electronic databases from PubMed, Web of Science, Embase, and CNKI. Articles related to the cytokine polymorphisms in patients with NPC and healthy controls from inception to 1 April 2024 were included. The results were analysed independently by two reviewers using RevMan 5.4 software. Summary odds ratio (OR) and 95% confidence interval (CI) were used to evaluate cancer risk. Results Our results showed that IL-10 1082A>G showed a significant difference only in the Dominant model, but in the Asian population, a significant difference was shown in all models. IL-18 607C>A polymorphism showed significant differences in the Allele model, Heterozygote model, and Homozygote model. In addition, the IL-18 137G>C polymorphism showed significant differences in all models. No statistically significant association was found between IL-8 251A>T, IL-10 819T>C polymorphism, and the risk of NPC. Conclusion Our meta-analysis results suggest that the IL-18 607C>A and IL-18 137G>C polymorphism are associated with the increased risk of NPC, and IL-10-1082 A/G polymorphism is associated with the increased risk of NPC in Asian populations.

关键词： engineered T cells   antibody-mediated rejection   solid organ transplantation   transplant rejection   alloreactivity   chimeric alloantigen receptor   CAR-T cells   alloreactive B cells   HLA   mismatch  

摘要： Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain. As proof-of-concept, CORA receptors based on HLA-A*02 were developed. In co-cultures with antiHLA-A*02 B cell lines, CORA-Ts were specifically activated, released pro-inflammatory mediators, and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLAA*02 antibody release. Significant reduction of growth of an anti-HLA-A*02 B cell line could be confirmed using an in vivo mouse model. Modification of the CORA receptor effectively abrogated T cell binding, thereby avoiding T cell sensitization. Additionally, using CRISPR-Cas9-mediated knockout of the FKBP12 gene, CORA-Ts were able to resist immunosuppressive treatment with tacrolimus, thereby allowing high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically eliminate alloreactive, anti-HLA B cells, thus selectively preventing anti-HLA antibody release even under immunosuppressive conditions. This suggests CORA-Ts as potent approach to combat AMR and improve long-term graft immunity.

关键词： T-cells  

摘要： BK polyomavirus (BKPyV) infection remains a major concern after kidney transplantation, increasing the risk of graft loss in the absence of specific antiviral agent now available. Here, we investigated the impact of HLA diversity on the control of posttransplant BKPyV replication. High HLA evolutionary divergence (HED) at the DQ locus in the donor was an independent predictor of BKPyV-free outcome. More generally, we highlighted the protective effect of highly divergent pairs of HLA-DQ heterodimers corresponding to heterozygous HLA-DQ alpha 01/non-DQ alpha 01 combinations. We then defined a functional divergence metrics assessed by the similarity of peptide-binding motifs between pairs of HLA-DQ molecules. Greater functional divergence correlated with the size of the BKPyV-derived DQ-bound immunopeptidome and a lower risk of BKPyV reactivation, thus providing a molecular basis for the observed genetic differences. Together, these data provide evidence for a direct link between donor HLA-DQ genetic and functional divergence, diversity of the DQ-bound immunopeptidome, and control of viral infection, likely reflecting stronger antiviral T cell responses.

关键词： 神经梅毒   白细胞介素-17   白细胞介素-22   转化生长因子-β1  

摘要： 目的探究神经梅毒患者外周血调节性T细胞(regulatory T cells，Treg)/辅助性T细胞17(helper T cells 17, Th17)、白细胞介素(interleukin, IL)-17、IL-22、转化生长因子-β1(transforming growth factor-β1, TGF-β1)水平变化情况。方法回顾性分析2020年5月至2022年5月在南京市第二医院皮肤科因梅毒就诊的135例梅毒患者的临床资料，依据有无神经系统累及将其分为神经梅毒组(65例)和非神经梅毒组(70例)，另选取同期在南京市第二医院健康体检者30例作为对照组，比较各组Treg/Th17、IL-17、IL-22、TGF-β1水平的差异性；依据病程分期将神经梅毒组患者分为早期组(28例)和晚期组(37例)，比较各组Treg/Th17、IL-17、IL-22、TGF-β1水平的差异性，并绘制受试者工作特征曲线分析Treg/Th17、IL-17、IL-22、TGF-β1识别早期神经梅毒的诊断效能。结果神经梅毒组、非神经梅毒组、对照组Treg、Treg/Th17、TGF-β1水平比较：[(34.00±12.03)%比(28.36±8.00)%比(21.85±8.23)%，(11.03±3.69)比(4.55±1.05)比(2.39±0.21)，(24.05±1.78)pg/mL比(20.15±2.03)pg/mL比(17.66±3.58)pg/mL，F值分别为16.37、179.24、95.52，P值均<0.001]；神经梅毒组、非神经梅毒组、对照组Th17、IL-17、IL-22水平比较：[(3.08±0.45)%比(6.23±1.00)%比(9.13±1.95)%，(25.69±3.33)pg/mL比(29.25±4.15)pg/mL比(34.00±6.75)pg/mL，(9.80±1.00)pg/mL比(14.30±2.18)pg/mL比(16.20±5.23)pg/mL，F值分别为342.67、36.55、74.39，P值均<0.001]。在Treg、Treg/Th17、TGF-β1水平比较上，早期组大于对照组[(29.45±6.78)%比(37.68±5.43)%，(6.91±2.31)比(30.63±6.96)，(21.36±2.00)pg/mL比(26.22±1.78)pg/mL，t值分别为5.44、17.30、10.34，P值均<0.001]；在Th17、IL-17、IL-22水平比较上，早期组大于晚期组[(4.26±1.00)%比(1.23±0.45)%，(28.00±2.15)pg/mL比(23.82±1.47)pg/mL、(12.00±3.64)pg/mL比(8.02±2.18)pg/mL，t值分别为16.40、9.31、5.48，P值均<0.001]。Treg/Th17、IL-17、IL-22、TGF-β1诊断神经梅毒的曲线下面积分别为0.774(0.676～0.853)、0.767(0.670～0.848)、0.737(0.637～0.822)、0.768(0.670～0.849)。结论神经梅毒患者外周血Treg/Th17、IL-17、IL-22、TGF-β1表达异常，且Treg/Th17、IL-17、IL-22、TGF-β1水平可以衡量患者病情的严重程度。