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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： Neutrophil extracellular traps   Barrier functions   Ulcerative colitis   Alzheimer's disease   Bioinformatics  

摘要： Ulcerative colitis (UC) and Alzheimer's disease (AD) share a common etiology as inflammatory diseases characterized by barrier deterioration. The aim of this study is to elucidate how neutrophil extracellular traps (NETs), serving as a comorbid etiological factor, can trigger the dysfunction in both the intestinal barrier and blood-brain barrier (BBB). Integrated bioinformatics analysis revealed 14 overlapped NETs-related differential expressed genes in UC and AD, which strongly featured barrier dysfunction. The following verification experiments identified enriched NETs, as well as damaged intestinal epithelium and BBB permeability, in the colon and prefrontal cortex of colitis mice and APP/PS1 mice. By employing pharmacological interventions (Cl-amidine and Disulfiram), we disrupted the formation of NETs and discovered significantly restored barrier integrity and attenuated inflammation. Further enrichment and correlation analysis indicated, for the first time, DDIT4/IL-1 beta NETs might drive macrophage-mediated phagocytosis to induce barrier dysfunction in UC and AD. Our findings originally established the peripheral-central inflammation interactions of UC and AD from the perspective of NETs, highlighting the potential valuable roles in gut-brain interactions and future clinic translational therapeutics.

关键词： COVID-19   Genetic susceptibility   Single nucleotide polymorphisms   Cytokines   Interleukin-6   Mexico  

摘要： Background COVID-19 was the leading cause of death in Mexico between 2020 and 2021. SARS-CoV-2 infection varies widely among individuals and populations. Since variations in genes related to the immune response may play a role in the susceptibility to and outcome of COVID-19, the associations of gene polymorphisms (SNPs) of IL-6 (- 573G > C, rs1800796), TNF-alpha (- 308G > A, rs1800629), and IFN-gamma (- 1615 C > T, rs2069705) with the expression levels of these proteins in the nasopharynx and serum were evaluated in a Mexican population with mild, severe, or critical COVID-19. Methods A total of 560 COVID-19 patients (309 mild, 163 severe, and 88 critical cases) and 560 age- and sex-matched COVID-19-negative controls were recruited for this case-control study. The selected SNPs were genotyped via allelic discrimination. Logistic regression analysis was conducted considering four models of inheritance, and ORs were determined for each genotypic variant, adjusting for associated comorbidities in the multivariate model. The nasopharyngeal mRNA expression levels of IL-6, IFN-gamma and TNF-alpha were determined. The levels of IL-6, IFN-gamma, IFN-alpha 2, and TNF-alpha in the serum were quantified. Significant differences were assessed via the Wilcoxon Mann-Whitney U test. Results The C allele of the IL-6 - 573 SNP was associated with a greater risk of mild and severe COVID-19 (OR: 2.3, CI: 1.897-2.838, p = 0.0001;and OR: 1.5, CI: 1.167-1.949, p = 0.002, respectively), whereas the A allele of the TNF-alpha - 308 SNP and the T allele of the IFN-gamma - 1615 SNP were shown protective roles against severe COVID-19 (OR: 0.3, CI: 0.189-0.537, p = 0.0001;and OR: 0.7, CI: 0.563-1.006, p = 0.05) and against critical COVID-19 (OR: 0.3, CI: 0.158-0.640, p = 0.001;and OR: 0.4, CI: 0.290-0.678, p = 0.0001), adjusting for diabetes and hypertension. Nasopharyngeal IL-6 expression levels were lower in mild COVID-19 patients (p = 0.001) than in critical patients (p = 0.005). Serum IL-6

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： Silicosis   TNF-Alpha   Fibrosis   Airway hyperreactivity   Thalidomide  

摘要： Inhalation of crystalline silica particles causes silicosis, which is a severe inflammatory lung disease that is associated with granulomatous and fibrotic responses. We investigated whether silica-induced silicosis might promote airway hyperreactivity (AHR) and the role of TNF-alpha and thalidomide in this process. Mice received an intranasal instillation of silica particles (1.25, 5, and 10 mg/mouse) and given methacholine on days 2, 7, and 28 after provocation or 5-HT challenges on day 7 after provocation. AHR was assessed using invasive whole-body plethysmography. Lung-tissue samples were collected for TNF-alpha measurements and histological analyses. Thalidomide was given orally from days 21-27 after silica administration. We found that following aerosolised methacholine or 5-HT treatment, a state of AHR was induced with silica-particle amounts of 5 and 10 mg/mouse, but not 1.25 mg/mouse. The effect was apparent within 2 days and remained for at least 28 days. Silica-particle amounts of 5 and 10 mg/mouse also induced significant granuloma response correlating with the silica required to induce AHR. In addition, a parallel was also observed between the elevation of lung tissue levels of TNF-alpha and AHR. Notably, silica-induced granulomatous and AHR responses were abolished in TNFR1- /- mice compared to wild-type mice. Moreover, the blockade of ongoing TNF-alpha generation by thalidomide prevented both events. Our findings suggest that exposure of mice to silica particles leads to a granulomatous lung response marked by nonspecific AHR induced by TNF-alpha. In addition, the results indicate that thalidomide can control silica-induced pathological features of the lungs by blocking TNF-alpha generation.

关键词： combination therapy   oncolytic adenovirus   TNF   TNFR2   tumor microenvironment  

摘要： Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.

关键词： NKT Cells  

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： Leprosy   Bangladesh   Genetics   Association study   Family-based  

摘要： Previous studies have demonstrated the association between the occurrence of leprosy and several host genetic variants that can vary across different ethnic groups and populations. Since leprosy susceptibility genes have not been investigated in detail in the Bangladeshi population that still includes highly endemic areas, we here studied known associations between leprosy and 13 genetic markers located in 11 genes in a leprosy endemic area in Bangladesh for which an association with leprosy was previously found in an isolated former leprosy colony in the Brazilian Amazon. For this study, a family-based analysis using 60 parent-affected child trios was performed, followed by a case-control study of 210 leprosy patients and 189 healthy controls from the same area (endemic controls). Genotypes for 11 markers were determined by TaqMan SNP genotyping. In the family-based study, a significant association was found between leprosy and three single nucleotide polymorphisms, rs1801224, rs13001714, and rs1801582, located in the CUBN, IL1RL1, and PRKN genes, respectively. These findings were not replicated in the case-control sample. Variants in the CUBN, IL1RL1, and PRKN genes were associated with leprosy in Bangladesh, validating the initial Brazilian finding in a population sample of distinct ethnic background.

关键词： IRF8   Common carp (Cyprinus carpio. L)   Poly I:C   Aeromonas hydrophila   IFN   NF-kappa B  

摘要： BackgroundInterferon (IFN) regulatory factors (IRF) are the crucial transcription factors for IFN expression and leading host cells response to viral infection. IRF8 in mammals plays vital roles in the innate and adaptive immune systems. In this study, we identified and characterized the common carp (Cyprinus carpio. L) IRF8 gene (ccIRF8) to further clarify the function of IRF8 in teleost fish. ResultsThe complete cDNA sequence of ccIRF8 was 1431 bp and encodes a polypeptide of 431 amino acids. Analysis of the putative amino acid sequence showed that ccIRF8 encodes structures typical of the IRF family, including a DNA-binding domain (DBD), an IRF-association domain (IAD) and two nuclear localization signals (NLS). Comparison with homologous proteins showed that the deduced protein has the highest sequence identity to grass carp IRF8 (92.7%). Phylogenetic analysis grouped ccIRF8 with other IRF8s of teleosts. Quantitative RT-PCR analysis showed that ccIRF8 transcripts were detectable in all investigated tissues of healthy fish with the highest level in spleen. Following poly I: C and Aeromonas hydrophila challenge, ccIRF8 transcripts were induced significantly in immune relevant tissues. In addition, ccIRF8 was induced by poly I: C and ipopolysaccharide (LPS), peptidoglycan (PGN) and flagellin in HKLs. Overexpression of ccIRF8 increased the expression of IFN and IFN-stimulated genes (ISGs), and a dual-luciferase reporter assay revealed that ccIRF8 decreased the activation of NF-kappa B though TRAF6. ConclusionsOverall, our findings provide a new perspective on the role of IRF8 in innate immunity in fish, as well as insights that will help the prevention and control of disease in the common carp farming industry.