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关键词： Jujube polysaccharides   Ulcerative colitis   Interleukin-33   Tumorigenicity 2 suppression   MYD88  

摘要： Jujube is a medicinal herb and daily food. Polysaccharides extracted from jujube possesses immune regulatory activity. In this study, we investigated whether jujube polysaccharides (JP) could ameliorate ulcerative colitis (UC), an inflammatory disease, and explore the potential mechanism of UC. We first extracted and characterized the structure JP, using dextran sulfate sodium-induced UC mice model to verify the pharmacological function. Research proved that JP treatment could ease UC mice symptoms and pathological injury. According to transcriptomics analysis, majority genes were enriched to cytokines-cytokines receptors signal pathway. Results showed that the increasing proinflammatory cytokines in UC mice colon were declined after JP intervention. Meanwhile, the receptor of interleukin-33 (IL-33), tumorigenicity 2 suppression (ST2) and downstream protein MYD88 expression in UC mice colon were corrected by JP intervention. As a result, according to immunohistochemistry detection, JP downregulated UC mice colon T cells expression (labeled by CD3+). We further employed flow cytometry to validate that JP could suppress CD4+ high expression on Jurkat cell stimulated by IL-33. In conclusion, JP could ameliorate UC mice symptoms, the mechanism of which was related to the regulation of IL-33/ST2 axis.

关键词： HLA   HLA-DPB1*29:01:02   new methods   NGS   novel allele  

摘要： HLA-DPB1*29:01:02 differs from HLA-DPB1*29:01:01 by a single synonymous substitution in exon 2.

关键词： Adalimumab   Arthritis   Inflammation   ELISA   Pharmacokinetics   Bioanalysis   TNF-Alpha  

摘要： Adalimumab, a humanized IgG1 monoclonal antibody is currently used to treat inflammatory diseases. However, a sensitive, in-house ELISA for evaluating inter-and intra-individual pharmacokinetic variability of adalimumab remains limited. In this study, an ELISA was developed to measure adalimumab levels, using recombinant human TNF-alpha (rhTNF-alpha) as capture antibody. Initially, surface plasma resonance showed acceptable binding kinetics (KD) of 2.38x10-07 nM for adalimumab. Next, a standard curve of adalimumab (1.54 ng/ml to 300 ng/ml), with five quality control points (5.2, 16, 27, 150, and 200 ng/ml) was evaluated for inter and intra-assay accuracy and precision, using serum matrix, by four independent validations. The linear range of the validated assay was 5.2 ng/ml to 200 ng/ml, upper limit of quantification (ULOQ) and lower limit of quantification (LLOQ) were 200 ng/ ml and 5.2 ng/ml, respectively. The assay specificity was validated by testing cross-reactivity of rituximab with rhTNF-alpha, which was found to be non-reactive. Further, the hook effect was over-ruled by diluting the highest concentration of adalimumab tested to assay linear range, and dilution integrity was observed for entire concentrations within linear range (%RE <= 20 %), as recommended by European Medicines Agency. Collectively, this rhTNF-alpha binding-based ELISA method is highly sensitive, reproducible, and useful for monitoring adalimumab.

摘要： Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, plays a critical role in intestinal homeostasis and inflammation and is strongly implicated in the pathogenesis of inflammatory bowel disease (IBD). Therapies targeting the p19 subunit of IL-23 have recently expanded the therapeutic options for IBD demonstrating efficacy and safety for the treatment of moderate to severe Crohn's disease (CD). Thus, in this review, we provide an overview of agents targeting the IL-23 pathway in CD, highlighting similarities and differences of specific IL-23 inhibitors. Furthermore, we summarize key phase 3 trials and head-to-head trials, focusing on design features and interpretation. Finally, we discuss the positioning of selective IL-23 agents for CD treatment along with areas of unmet clinical needs. However, real-world data will offer additional comparative effectiveness information, data for disease subtypes, and insights into the long-term outcomes of IL-23 inhibition. Looking ahead, ongoing phase 3 studies testing p19-specific selective IL-23 inhibitors are expected to expand the therapeutic options for patients with complex phenotypes, including those with extraintestinal manifestations (EIMs), fistulas, and strictures. Advances in molecular and cellular characterization, including the development of predictive molecular biomarkers, may help guide clinical decision-making, enabling more personalized treatment approaches. Precision medicine studies may further enhance our understanding of the molecular biology of IL-23, shedding light on how these agents work in complex CD and clarify their potential complementary or synergistic effects with other therapies.

关键词： IL-12   Immunotherapy   cancer   uPAR/CD87/PLAUR   Tumor-targeting   Immune-oncology  

摘要： IL-12, also called IL-12p70, is a highly potent, proinflammatory heterodimeric cytokine that can mediate many beneficial anti-tumor effects. In preclinical studies, recombinant IL-12, as well as IL-12 gene therapies, have demonstrated notable anti-tumor results across various tumor types;however, IL-12 clinical benefit has been limited by its poor tolerability at potentially efficacious doses. We have developed a novel approach to mitigate the toxicity of IL-12 by engineering tumor-targeted split IL-12 that preferentially localizes IL-12 activity to the tumor microenvironment. The functionally inactive IL-12 subunits, p35 and p40, are separately fused to antibody fragments targeting a highly expressed tumor-associated antigen, uPAR. The goal of this strategy is to drive assembly and activity of the IL-12 heterodimer into the tumor site through sequential administration of the targeted subunits, reducing systemic exposure and thereby potentially reducing associated toxicities. We use in vitro activity assays along with in vivo pharmacokinetic and pharmacodynamic studies in mice and non-human primates to demonstrate that the split IL-12 anti-uPAR fusions are capable of assembly and activity in vivo. The targeted p35 and p40 subunits are capable of complexing to form IL-12p70 and inducing STAT4 phosphorylation when applied to cultured immune cells, indicating in vitro IL-12 activity. Furthermore, sequential administration of subunits in in vivo mouse models demonstrates rapid serum clearance of IL-12 while extending retention in the tumor. Finally, dosing in non-human primates shows molecules are functionally active in vivo. This is a unique strategy with great clinical promise to harness the therapeutic potential of IL-12 while potentially avoiding the toxicity associated with systemic delivery.

关键词： Immunogenetics   Autoimmunity   Hepatitis   Sclerosing cholangitis   Regulatory T cells   Human study  

摘要： Background & aims: Juvenile autoimmune liver disease (JAILD) comprises autoimmune hepatitis and autoimmune sclerosing cholangitis. JAILD-predisposing genes include HLA-DR3,DR7, DR13 and haplotype A1-B8-DR3. Mechanisms leading to liver autoimmunity remain elusive, though JAILD patients have aberrated immunoregulation. We investigated the influence of HLA genes on immune cells, focusing on T-cells and frequency and function of T regulatory cells (Tregs) in JAILD patients, their first-degree-relatives (FDRs) and healthy controls (HCs). Methods: HLA class I and II genotypes were defined by PCR and peripheral blood mononuclear cells were immunophenotyped by FACS in 82 patients, 72 FDRs, 50 HCs. Treg function was tested by inhibition of CD4posCD25neg T-cell proliferation. Links between HLA genes, Treg frequency/function, pro-inflammatory/ immunoregulatory cytokines, soluble and membrane-bound programmed cell death-1 (PD-1) were investigated. Results: Proportion of subjects carrying HLA DR3/DR7/DR13 was 88 %, 92 %, 64 % in patients, FDRs and HCs. Circulating Treg frequency was lower in patients and FDRs than HCs. Inhibitory capacity of Tregs was lower in patients but similar in FDRs compared to HCs. FDRs possessing HLA DR3/DR7/DR13 genes had Treg frequencies lower than those without. PD-1 posCD4pos T-cells were fewer in patients than HCs;PD-1posCD8pos T-cells were fewer in patients and FDRs than HCs. Patient plasma levels of IFN-gamma were higher, and ratios of IFN-gamma/IL-10 and IFN-gamma/IL-2 lower than in HCs. All nine FDRs with autoimmune disorders had HLA DR3/DR7/DR13 genes and lower Treg frequency than those without autoimmune disorders and HCs. Conclusion: We show a link between HLA disease-predisposing genes and defective immunoregulation not only in JAILD patients, but also in their FDRs, who are prone to autoimmune disorders.

关键词： confirmatory allele   HLA-DQA1*05:82   NGS  

摘要： We report a confirmatory HLA-DQA1*05:82 allele detected in a Chinese individual.

关键词： Dendritic cells   Skin transplantation   Regulatory B cells   CD 169   NF-kappa B  

摘要： Skin allografts are prone to rejection because of their high immunogenicity. By achieving immune tolerance, the long-term survival of skin allografts can be extended without the need for immunosuppressants or with only short-term low-dose dependency. Tolerogenic dendritic cells (tolDCs) show a strong potential for graft tolerance. We explored the mechanism whereby rapamycin-modified CD169low/-tolDCs regulate interleukin-10 (IL-10) B regulatory (IL-10+ Breg) cell production and mediate the long-term survival of skin allografts in mice. CD169low/-tolDCs were obtained through flow cytometry sorting after treating the mesenchymal stem cell (MSC)-derived dendritic cells with a low dose of GM-CSF. A treatment regimen combining preoperative stimulation and postoperative adoptive infusion of CD169low/-tolDCs was used to treat an acute rejection (AR) mouse skin transplantation model-the adoptive infusion group. An equivalent dose of saline was administered to the control group. Survival and graft rejection rates were assessed. Mixed lymphocyte culture, flow cytometry, immunohistochemistry (IHC), and western blotting (WB) were used to elucidate the expression of different IL10+ Breg subsets in mice treated with adoptive infusion therapy and the molecular mechanisms whereby CD169low/-tolDCs induce IL-10+ Breg production to mediate tolerance. Adoptive infusion of CD169low/-tol DCs markedly prolonged the rejection time after skin transplantation in mice and promoted graft survival. A significant increase was observed in local blood flow signals in the transplanted skin, along with mild local inflammation. Flow cytometric analysis revealed a positive correlation between high expression of IL-10+ Breg and the changes in Foxp3+ Tregs in vivo, primarily enriched in the CD19 + CD24 + CD27+ mBreg and CD19 + CD23 + CD27-CD24+ Breg subsets, with higher levels of IgM expression. Significant differences were observed compared with control mice. CD79b/NF-kappa B pathway was found to be inv

摘要： The term mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome was initially dubbed by Firestein et al. in 1985. He described five patients with clinical manifestations of Behcet's disease (BD) as well as relapsing polychondritis (RP), putting forward the terminology MAGIC syndrome to describe the overlap of the two diseases. Thereafter, not many cases have been documented in the literature. In our case, a 20-year-old male fulfilled the criteria for BD as well as RP and was diagnosed with MAGIC syndrome. Human leukocyte antigen (HLA) typing showed HLA-B51 positivity. He was effectively treated with oral colchicine and oral prednisolone. The patient's symptoms recovered gradually, and prednisolone was tapered and stopped. The exact pathophysiology behind MAGIC syndrome is still unestablished, and the number of cases reported is not sufficient enough to indicate an apparent explanation. Hence, accretion of additional cases and supplementary research is required to enhance the comprehension of MAGIC syndrome.