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摘要： Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-kappa B, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-kappa B target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-kappa B target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms.

摘要： Highlights•There is no standard treatment in NSCLC and acquired resistance to immunotherapy. •OSE2101, a therapeutic cancer vaccine, demonstrated survival benefit in this setting. •We present the design of the phase 3 trial to confirm initial positive results.

关键词： Crohn's disease   elderly   anti-TNF   ustekinumab   safety   effectiveness  

摘要： Background Biologic therapies are associated with increased infection risk among elderly patients with inflammatory bowel disease (IBD). However, there are few data on the safety and effectiveness of ustekinumab compared with anti-tumor necrosis factor (anti-TNF) agents in the *** The study sought to compare the safety and effectiveness of ustekinumab and anti-TNF agents in elderly Crohn's disease (CD) patients. Patients >= 60 years of age who commenced ustekinumab or an anti-TNF agent for CD were included in this retrospective multicenter cohort. The primary outcome was incidence of serious infections requiring hospitalization. Effectiveness was assessed by clinical remission, clinical response, and treatment persistence rates at 6 months. We adjusted for confounders using inverse probability of treatment weighting (IPTW) and performed a logistic regression analysis to assess factors associated with serious infections, clinical remission, and treatment *** Eighty-three patients commencing ustekinumab and 124 commencing anti-TNF therapy were included. There was no difference in serious infection rates between anti-TNF agents (2.8%) and ustekinumab (3.1%) (P = .924) after propensity adjustment. Clinical remission rates were comparable at 6 months for ustekinumab (55.9%) and anti-TNF agents (52.4%) (P = .762). There was a significant reduction in HBI at 6 months in both groups. Treatment persistence was comparable between ustekinumab (90.6%) and anti-TNF agents (90.0%) at 6 months. Cox regression analysis did not show differences in treatment persistence (hazard ratio, 1.23;95% confidence interval, 0.57-2.61;P = .594) and serious infection incidence (hazard ratio, 1.38;95% confidence interval, 0.25-7.57;P = .709) by 6 *** We observed comparable safety and effectiveness for ustekinumab and anti-TNF agents in treating elderly CD patients. In this retrospective multicenter cohort study, we report equal safety and effectiveness f

关键词： deep learning   evolutionary scale model   human leukocyte antigen   peptide   prediction  

摘要： The recognition of endogenous peptides by HLA class I plays a crucial role in CD8+ T cell immune responses and human adaptive cell immune. Thus, the prediction of HLA class I-peptide binding affinities is always the core issue for the research of immune recognition and vaccine development. In this study, an evolutionary scale model (ESM) combined with parallel CNN blocks and a cross attention mechanism was used to construct a novel ESMpHLA model for predicting HLA class I binding peptides. Based on the 91,560 binding peptides of 41 HLA-A alleles, 56,731 of 50 HLA-B alleles and 2444 of 10 HLA-C alleles, the ESMpHLA model was successfully established and achieved satisfying prediction performances with the overall accuracy and AUC values of 0.874 and 0.938 for the test dataset. The results indicate that the ESMpHLA model performs well in dealing with different HLA class I 2-field alleles as well as the peptides with different lengths. Then, the generalisation ability of the ESMpHLA model was validated by an independent test dataset compiled from recent IEDB weekly benchmark datasets. The results showed that the ESMpHLA model achieved the highest ROC-AUC and PR-AUC values when compared with the latest BVMHC, CapsNet-MHC, STMHCpan and BVLSTM models. In addition, two ensemble models were also established by integrating the above 5 deep learning models using soft-voting and hard-voting strategies.

关键词： Viruses   Epstein-Barr virus (EBV) BSRF1   Cellular moleculars   Antiviral response   Protein-protein interaction   NF-kappa B signaling pathway  

摘要： The Epstein-Barr virus (EBV) encoded tegument protein BSRF1 plays a significant role in the processes of viral maturation and release, however, it's not clear whether BSRF1 is involved in the modulation of host innate immunity. In this study, we demonstrated that BSRF1 can inhibit interferon beta (IFN-beta) production by down- regulating nuclear factor kappa B (NF-kappa B) activity and subsequently reducing the yield of inflammatory cytokines, thereby facilitating viral replication. Dual luciferase reporter assays indicated that BSRF1 may inhibit NF kappa B signaling at the level of IKK or between IKK and p65, while co-immunoprecipitation experiments revealed its association with multiple critical host adaptor proteins. Mechanistically, BSRF1 hinders the phosphorylation of I kappa B alpha at Ser32/36 and K48-linked polyubiquitination, thereby preventing proteasome-mediated degradation of I kappa B alpha by disrupting the assembly of the regulatory subunits within the IKK complex. Although BSRF1 interacts with p65 and its N-terminal domain, it does not alter the formation of the p65/p50 heterodimer. Instead, it prevents the nuclear translocation of p65 by inhibiting the dissociation of I kappa B alpha from the NF-kappa B dimer. Collectively, these findings suggested that BSRF1 assists EBV's evasion of host innate immune system by inhibiting the antiviral response to IFN-beta through the NF-kappa B signaling pathway, potentially contributing to the virus's ability to establish persistent infection and its association with tumorigenesis.

关键词： HLA-DRB1   NGS   novel allele  

摘要： Five novel HLA-DRB1 alleles, HLA-DRB1*03:219, HLA-DRB1*04:171:02, HLA-DRB1*04:392, HLA-DRB1*11:01:52 and HLA-DRB1*11:342, were identified.

关键词： iPSC   Chimeric Antigen Receptor   Dendritic cell  

摘要： Background & AimImmunotherapy based on T cells expressing CARs has been shown to be a promising strategy for treating hematological tumors. However, similar results have not been reported for solid tumors. Therefore, other immune cells have been explored to express CARs for immunotherapy applications. Dendritic cells are a heterogeneous cell population specialized in antigen presentation, with great migratory capacity, representing good candidates for solid tumor therapies. Due to their scarcity in peripheral blood and low proliferative potential, an " off-the-shelf" source such as induced pluripotent stem cells is needed to enable their use in cell therapy. Thus, our aim is to develop iPSC-DCs expressing CAR as an alternative treatment for solid tumors. MethodologyElectroporation of the piggyBac transposon system was utilized to insert a CAR into an iPSC line. Differentiation of CAR-iPSCs was carried out following an established step-by-step protocol: (A) embryoid body formation, (B) generation of hematopoietic stem-like cells and (C) production of immune myeloid-like cells. Subsequently, differentiation into myeloid immune cells was induced using GM-CSF and IL-4 after 30 days. Flow cytometry was employed to analyze the phenotype of the differentiated cells. Co-culture of CAR-iPSC-DC cells with T cells was performed to observe induction of T cell proliferation. ResultsWe have achieved an initial transfection efficiency of 2%. Sequential cell sorting increased the purity of CAR-expressing cells to 95%, with stable expression maintained for over 40 days. We obtained differentiated cells with typical myeloid immune cell morphology, including a few macrophage-like cells, with large cytoplasmic vacuoles and numerous cells with dendrite projections, closely resembling DC morphology. Moreover, cells presented a HLA-DR+CD64lowXCR1high phenotype, similar to cDC1 found in PB. Preliminary data showed that these cDC1-like cells are able to induce CD3+ T cell proliferation in v