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关键词： HCC   GPC3   CAR-T   IL-21   CXCL9   PD-1  

摘要： The application of CAR-T cells in solid tumors poses several challenges, including poor T cell homing ability, limited infiltration of T cells and an immunosuppressive tumor environment. In this study, we developed a novel approach to address these obstacles by designing GPC3-specific CAR-T cell that co-express IL-21 and CXCL9 (21 x 9 GPC3 CAR-T cells) and blocking the PD-1 expression on it. The proliferation, cell phenotype, cytokine secretion and cell migration of indicated CAR-T cells were evaluated in vitro. The cytotoxic activities of genetically engineered CAR-T cells were accessed in vitro and in vivo. Compared to conventional GPC3 CAR-T cells, the 21 x 9 GPC3 CAR-T cells demonstrated superior proliferation, cytokine secretion and chemotaxis capabilities in vitro. Furthermore, when combined with PD-1 blockade, the 21 x 9 GPC3 CAR-T cells exhibited enhanced proliferation, cytokine secretion and enrichment of effector T cells such as CTL, NKT and TEM cells. In xenograft tumor models, the PD-1 blocked 21 x 9 GPC3 CAR-T cells effectively suppressed HCC xenograft growth and increased T cell infiltration. Overall, our study successfully generated GPC3 CAR-T cells expressing both IL-21 and CXCL9, demonstrated that combining PD-1 blockade can further enhance CAR-T cell function by promoting proliferation, cytokine secretion, chemotaxis and antitumor activity. These findings present a hopeful and potentially effective strategy for GPC3-positive HCC patients.

关键词： type II alveolar epithelial cell   macrophage   lung regeneration   fibrosis   IL4R signaling   CP: Stem cell research  

摘要： Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.

关键词： COVID-19   Omicron variants   HLA-B*15   vaccination   SARS-CoV-2  

摘要： Background Natural infection or vaccination have provided robust immune defense against SARS-CoV-2 invasion, nevertheless, Omicron variants still successfully cause breakthrough infection, and the underlying mechanisms are poorly *** Sequential blood samples were continuously collected at different time points from 252 volunteers who were received the CanSino Ad5-nCoV (n= 183) vaccine or the Sinovac CoronaVac inactivated vaccine (n= 69). The anti-SARS-CoV-2 prototype and Omicron BA.5.2 as well as XBB.1.16 variant neutralizing antibodies (Nab) in sera were detected by ELISA. Sera were also used to measure pseudo and live virus neutralization assay. The associations between the anti-prototype Nab levels and different HLA-ABC alleles were analyzed using artificial intelligence (AI)-deep learning techniques. The frequency of B cells in PBMCs was investigated by flow cytometry assay (FACs).Results Individuals carrying the HLA-B*15 allele manifested the highest concentrations of anti-SARS-CoV-2 prototype Nab after vax administration. Unfortunately, these volunteers are more susceptible to Omicron BA.5.2 breakthrough infection due to their sera have poorer anti-BA.5.2 Nab and lower levels of viral neutralization efficacy. FACs confirmed that a significant decrease in CD19+CD27+RBD+ memory B cells in these HLA-B*15 population compared to other cohorts. Importantly, generating lower concentrations of cross-reactive anti-XBB.1.16 Nab post-BA.5.2 infection caused HLA-B*15 individuals to be further infected by XBB.1.16 *** Individuals carrying the HLA-B*15 allele respond better to COVID-19 vax including the CanSino Ad5-nCoV and the Sinovac CoronaVac inactivated vaccines, but are more susceptible to Omicron variant infection, thus, a novel vaccine against this population is necessary for COVID-19 pandemic control in the future.

关键词： HLA   immunogenetics   TCR   personalized medicine   precision medicine  

摘要： HLA traveled a long distance from initially being regarded as a transplant antigen to becoming a molecule of interest in 21 st century for the development of novel diagnostics and therapeutics in the treatment of human diseases, vaccine design, pharmacogenetics, and genomics. The proteins encoded by genes in the Human Leukocyte Antigen (HLA) complex regulate the innate and adaptive arms of human immune responsiveness through antigen recognition and presentation, inflammation regulation, and the complement system, and the impact of this region is well documented in solid organ and hematopoietic stem cell transplantation and various immune-mediated conditions. In the 21 st century, the role of HLA in personalized medicine is tailored with the advent of massive parallel sequencing technologies such as targeted sequencing by next-generation sequencing (NGS) and third-generation sequencing (TGS), which opens new frontiers in the development of predictive and preventive medicine. The goal of our research topic was to collect articles that provide the most cutting-edge research on the application of the concept of HLA in personalized medicine in the context of clinical allotransplantation and *** collection of articles in Frontiers in Genetics under the specialty research topic of "HLA in Personalized Medicine" presents three original research papers, one case report, and one perspective article. The research topic was open between September 9 th , 2023, and February 13 th , 2024, and five manuscripts were accepted for publication. The collection of this issue provides an important insight into the application of the concept of HLA in personalized medicine by presenting articles that demonstrate the significance of heterozygous advantages in cancer, the application of vaccination with a cocktail of HLA class I and II peptides in treating metastatic cancer, HLA-B and TAP transcriptional silencing in pediatric solid cancers, the utility of race, ethnicity, a

关键词： hepatitis B reactivation   anti-IL-17   anti-IL-12/23   anti-IL-23   JAK-inhibitors  

摘要： Objectives HBV reactivation (HBVr) constitutes a side effect of the treatment of autoimmune rheumatic diseases. Even though HBVr risk of conventional synthetic DMARDs (csDMARDs) and anti-tumor necrosis factor (anti-TNF) agents has long been established, the risk of targeted synthetic (ts)DMARDs and anti-interleukin (anti-IL) agents remains largely unknown. Methods We conducted a SLR (PubMed, Scopus and EMBASE) and meta-analysis to examine the HBVr risk for the following: anti-IL17, anti-IL12/23, anti-IL23 and JAK-inhibitors in patients with chronic HBV infection (HBsAg presence or detectable HBV-DNA) and in patients with prior HBV infection (HBcAb-positive and HBsAg-negative). Meta-analysis was performed using both the fixed and random effects method and was conducted using the R computing language. Results Overall, our study revealed a low HBVr risk of <6% in all agents;the risk was significantly higher for people having chronic compared with those with resolved HBV (14.4% vs 5.1%, respectively P < 0.01). There was no difference among different drugs in the HBVr rates [anti-IL-17: 4% (95% CI: 1-9%), anti-IL-12/IL-23: 2% (95% CI: 0-5%), JAK-inhibitors: 4% (95% CI: 1-8%), anti-IL23: 0%]. Of note, HBVr rate reached 28% in patients with chronic HBV who did not receive anti-viral treatment. For patients with resolved hepatitis, the respective percentage was 4.7%. Conclusion Overall, our meta-analysis shows that patients with chronic HBV receiving anti-IL-17, anti-IL-12/23, anti-IL-23 and JAK-inhibitors have significant risk for HBVr, especially if they are not under anti-viral treatment. In contrast, resolved HBV seems to offer minor risk for HBVr even without anti-viral treatment.

关键词： eosinophils   IL-4Rα   Heligmosomoides polygyrus   mesenteric lymph node   fibroblastic reticular cells   lymphatic endothelial cells   stromal cells   IL-33   CCL24   B cell   CP: Immunology  

摘要： Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Ra a or lymphotoxin-b b (LTb) b ) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-b b receptor (LTbR) b R) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient D dblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

摘要： mRNA vaccines against SARS-CoV-2 have revolutionized vaccine development, but their immunological mechanisms are not fully understood. Here, we investigate injection site responses of mRNA vaccines by generating a comprehensive single-cell transcriptome profile upon lipid nanoparticle (LNP) or LNP-mRNA challenge in female BALB/c mice. We show that LNP-induced stromal pro-inflammatory responses and mRNA-elicited type I interferon responses dominate the initial injection site responses. By tracking the fate of delivered mRNA, we discover that injection site fibroblasts are highly enriched with the delivered mRNA and that they express IFN-beta specifically in response to the mRNA component, not to the LNP component of mRNA vaccines. Moreover, the mRNA-LNP, but not LNP alone, induces migratory dendritic cells highly expressing IFN-stimulated genes (mDC_ISGs) at the injection site and draining lymph nodes. When co-injected with LNP-subunit vaccine, IFN-beta induces mDC_ISGs at the injection site, and importantly, it substantially enhances antigen-specific cellular immune responses. Furthermore, blocking IFN-beta signaling at the injection site significantly decreases mRNA vaccine-induced cellular immune responses. Collectively, these data highlight the importance of injection site fibroblasts and IFN-beta signaling during early immune responses against the mRNA vaccine and provide detailed information on the initial chain of immune reactions elicited by mRNA vaccine injection. The initial immune response following mRNA vaccine injection is not entirely clear. Here, the authors comprehensively profile injection site responses using single-cell transcriptomics in a mouse model showing activation of major axes of innate immune responses upon and the role of IFN-beta to promote cellular immunity.

关键词： HLA-C   epigenetic   nutrition   methylation   inheritance  

摘要： Environment and lifestyle can affect the epigenome passed down from generation to generation. A mother's nutrition can impact the methylation levels of her offspring's epigenome, but it's unclear which genes may be affected by malnutrition during gestation or early development. In this study, we examined the levels of methylated GC in the promoter region of HLA-C in mothers and infants from the Kichwa community in Ecuador. To do this, we analyzed saliva samples using bisulfite DNA sequencing. While we did not observe any significant differences in the mean methylation percentages in exon 1 of HLA-C between mothers and their infants after the first two years of lactation and life, respectively, we did find that infants tended to increase their methylation level during the first two years of life, while mothers tended to decrease it after the first two years of breastfeeding. When we compared methylation levels between mothers and infants using an ANOVA/posthoc Tukey test, we found that the average methylation for the entire population was less than 3% at T1 and T2. Although there was a tendency for infants to have higher methylation levels during their first two years of life and for mothers to have lower methylation levels after the first two years of breastfeeding, the mean values were not significantly different. However, we found a significant difference when we contrasted the data using a Kruskal-Wallis test at 0.05 for T1 AND T2 (p-value: 0.0148). Specifically, mothers had an average of X = 2.06% and sons had X = 1.57% at T2 (p-value: 0.7227), while the average for mothers was X = 1.83% and for sons X =1.77%. Finally, we identified three CpG motif nucleotide positions (32-33, 43-44, and 96-97) along the 122 bp analysis of HLA-C exon one, which was found to retain methylation patterns over time and is inherited from mother to offspring. Finally, our small pilot study did not reveal significant correlations between maternal and offspring nutritional status and DN

摘要： Retraction: Effects of dexmedetomidine on postoperative delirium and expression of IL-1, IL-6, and TNF-α in elderly patients after hip fracture operation Please find the retraction statement below: Zhang W, Wang T, Wang G, Yang M, Zhou Y and Yuan Y (2020) Effects of Dexmedetomidine on Postoperative Delirium and Expression of IL-1β, IL-6, and TNF-α in Elderly Patients After Hip Fracture Operation. Front. Pharmacol. 11:678. doi: 10.3389/fphar.2020.00678 The journal retracts the 12 May 2020 article cited above. Following publication, concerns were raised regarding the clinical trial registration for this study. An investigation was conducted in accordance with Frontiers’ policies, and it was confirmed that, contrary to the statements in the article, the study was not an accurate reflection of the study registered with the clinical trial registry. Lack of appropriate clinical trial registration is a breach of Frontiers’ guidelines and those of the Committee on Publication Ethics. As such, this article is being retracted. The authors received a communication regarding the retraction and had a chance to respond. This communication has been recorded by the publisher. Frontiers would like to thank Prof. John Loadsman for contacting the journal regarding the published article.

关键词： Mycobacterium tuberculosis (M.tb)   TB   LTBI   IL-10   IL-17   IFN-gamma   HBHA  

摘要： Background: To effectively control tuberculosis (TB), it is crucial to distinguish between active TB disease and latent TB infection (LTBI) to provide appropriate treatment. However, no such tests are currently available. Immune responses associated with active TB and LTBI are dynamic and exhibit distinct patterns. Comparing these differences is crucial for developing new diagnostic methods and understanding the etiology of TB. This study aimed to investigate the relationship between pro- and anti-inflammatory CD4+ cytokine production following stimulation with two types of latency-associated Mycobacterium tuberculosis (***) antigens to allow differentiation between active TB and LTBI. Methods: Cryopreserved PBMCs from patients with active TB disease or LTBI were stimulated overnight with replication-related antigen [ESAT-6/CFP-10 (E/C)] or two latency-associated antigens [heparin-binding hemagglutinin (HBHA) and alpha-crystallin-like protein (Acr)]. Responses were analyzed using multiparameter flow cytometry: active TB disease (n=15), LTBI (n=15) and ELISA: active TB disease (n=26) or LTBI (n=27). Results: CD4+ central memory T cells (Tcm) specific to E/C and CD4+ effector memory T cells specific to Acr and HBHA were higher in LTBI than in TB patients. IFN-gamma+Tcm and IL-17+ Tem cells was higher in the LTBI group (p= 0.012 and p=0.029 respectively), but IL-10+ Tcm was higher in the active TB group (p= 0.029) following HBHA stimulation. Additionally, following stimulation with HBHA, IL-10 production from CD4+ T cells was significantly elevated in patients with active TB compared to those with LTBI (p= 0.0038), while CD4+ T cell production of IL-17 and IFN-gamma was significantly elevated in LTBI compared to active TB (p= 0.0076, p< 0.0001, respectively). HBHA also induced more CCR6+IL-17+CD4Tcells and IL-17+FoxP3+CD25+CD4Tcells in LTBI than in TB patients (P=0.026 and P=0.04, respectively). HBHA also induced higher levels of IFN-gamma+IL-10+CD4+ T cells in patien