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关键词： Oropouche   Culicoides   Arbovirus   Emerging disease   Schmallenberg disease   Bluetongue   Epizootic haemorrhagic disease of cattle   A single health system  

摘要： The recent spread of the Oropouche virus (OROV), which causes a febrile dengue-like disease in humans in previously non-endemic areas of Central and South America and the Caribbean, the identification of maternal-foetal transmission and the first reports of deaths due to disease caused by this arbovirus have raised concerns about the greater threat posed by this agent to neighbouring countries (French Caribbean territories) and the Americas, including the United States. The risk of expansion also concerns Europe, insofar as the virus was documented in 2024 in human cases imported on return from a stay in Brazil or Cuba. The OROV virus is transmitted by a number of different vectors, mainly by Culicoids or biting midges. By analogy, over the last two decades, three exotic arboviruses (including an Orthobunyavirus, from the same family as OROV) transmitted by Culicoids, introduced and then established in Europe, have been responsible for epizootic outbreaks in livestock. These are the agents responsible for bluetongue, Schmallenberg disease and epizootic haemorrhagic disease of cattle. These events have demonstrated the possibility of an autochthonous vector relay in ruminants. In terms of anticipation, the risk of the OROV virus establishing itself in Europe cannot be formally ruled out during the next seasonal period of biting midge activity. It is also important to gain a better understanding of the possibilities for the introduction or spread within a country of these emerging viruses transmitted by Culicoids in both veterinary and human medicine. (c) 2025 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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.

关键词： Relapsing-remitting multiple sclerosis   RRMS   oncostatin M   IL-35   IL-39   multiple sclerosis  

摘要： Background: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory demyelinating disease of the central nervous system (CNS). Hence, there is a need to identify more biomarkers that may assist in developing new therapeutic strategies. This study aims to compare the levels of interleukin (IL)-35, IL-39, and oncostatin M (OSM) in patients with relapsing-remitting MS (RRMS) and healthy controls. Methods: Blood samples were collected from 38 patients with RRMS and 36 healthy individuals who served as a control group to measure the levels of the cytokines under study. The plasma levels of IL-35, IL-39, and OSM were measured and compared between the two groups using enzyme-linked immunosorbent assay (ELISA). Additionally, the expression of these cytokines was evaluated using reverse transcription polymerase chain reaction (RT-PCR). Results: Our results showed that RRMS is associated with higher levels of OSM and IL-39 and lower levels of IL-35 compared to healthy subjects. The results demonstrated that the levels of OSM and IL-39 in RRMS patients were significantly reduced by IFN-beta therapy. EDSS scores and IL-35 levels were found to be negatively correlated, while OSM levels and EDSS scores showed a positive and significant correlation. Statistical analysis revealed no significant relationship between IL-35, IL-39, and OSM plasma levels and factors such as age, gender, education level, and job. Conclusion: Elevated levels of OSM and IL-39 and decreased levels of IL-35 in RRMS patients suggest their potential as biomarkers for disease activity and progression. The correlation between these cytokines and EDSS scores further supports their relevance. Future research should focus on further elucidating the roles of these cytokines in RRMS and exploring their potential as therapeutic targets.

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： 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： Disease-modifying Drugs (DMARDs)   biological DMARD   Randomised controlled trial   Clinical Trial  

关键词： Coronary microcirculation   Ischaemia-reperfusion injury   Interleukin-36   Hyperglycaemia   Inflammation  

摘要： Following myocardial infarction (MI), patients with type 2 diabetes mellitus (T2DM) have poorer prognosis which may be linked to increased susceptibility of coronary microvessels to injury. Interleukin-36 (IL-36) may mediate this injury but its role in the microcirculation of the chronically hyperglycaemic injured heart is unknown. Intravital and laser speckle imaging of the anaesthetised mouse beating heart evaluated the impact of a 16-week high fat diet (HFD)-induced hyperglycaemia +/- myocardial ischaemia-reperfusion injury (IR) injury on coronary microvessels. Neutrophil/platelet recruitment, neutrophil extracellular trap formation, cellular necrosis, vascular leakage, vascular tonal changes, functional capillary density, overall ventricular perfusion and levels of circulating inflammatory cytokines were assessed alongside the vasculoprotective ability of an IL-36 receptor antagonist (IL-36Ra). Whether heightened microvessel damage in injured HFD mice was permanent or reversible was investigated after normalising hyperglycaemia through diet reversal (DR). Microcirculatory events assessed were perturbed basally in HFD mice and further after injury. IL-36Ra mitigated these effects and improved infarct size. DR was also beneficial, decreasing neutrophil recruitment to levels below those seen in untreated mice. Mechanistically, benefits of both IL-36Ra and DR could be explained by decreased endothelial oxidative stress and VCAM-1 expression and possibly by raised levels of IL-4/IL-13. Basal changes in chronically hyperglycaemic coronary microvessels that are heightened in the aftermath of reperfusion may explain the poorer outcomes in MI patients with T2DM. These findings are the first to highlight the specific benefits of IL-36 inhibition and reversing hyperglycaemia through dietary modification on the coronary microcirculation in a preclinical model of T2DM.

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： confirmatory allele   HLA-DQA1*05:82   NGS  

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