课程文献中心 更多>>

关键词： IL-1 targeted therapies   anakinra   canakinumab   major congenital malformation   neonatal outcomes   pregnancy   teratology information service  

摘要： OBJECTIVE:To describe the outcomes of pregnancies exposed to IL-1 targeted therapies (anti-IL-1): anakinra and/or canakinumab. METHODS:We performed a descriptive observational study based on data from CRAT, the French Teratology Information Service. We included prospective and retrospective pregnancies exposed to anakinra and/or canakinumab with known outcomes. Pregnancy, fetal and neonatal outcomes were analyzed. RESULTS:Between 2007-2023, 57 pregnant women exposed to anti-IL-1 were referred, including 27 (47.3%) treated for Still's disease. Among prospective cases, 52 fetuses (one twin pregnancy) were exposed to anakinra (n = 43), canakinumab (n = 5) or both medications (n = 4). For anakinra: i) 40/47 cases (85.1%) were exposed during the first trimester (T1), and 21/47 (44.7%) during all pregnancy, ii) 40/47 (85.1%) resulted in livebirths, 5/47 (10.6%) early miscarriages, one medical abortion (mother-transmitted syndrome) and one elective abortion iii) one isolated hypospadias was reported (anakinra between 0-4 weeks of gestation), for a prevalence of major congenital malformation of 3,03% IC95%[0.1-15.1] among T1-exposed pregnancies. For canakinumab, all cases (9/9) were exposed during T1 and 2/9 during all pregnancy: all resulted in livebirths with no malformation. Concerning retrospective pregnancies (anakinra = 6/6), all resulted in live births. Cardiopathy with hypospadias was identified in a child with a rare genetic anomaly. No significant effects were reported while breast-feeding (n = 9). CONCLUSION:In this study, the largest series to date, our results do not suggest occurrence of specific negative outcomes in pregnancies exposed to anti-IL-1. The imputability of anakinra in the malformations observed is unlikely. If needed, their use during pregnancy should be considered.

关键词： Mesenchymal stromal cells   autoimmune disease   immunomodulation   standardization   clinical trial design   data reporting   AD   Autoimmune disease   AT   Adipose tissue   ATMP   Advanced therapeutic medicinal product   BM   Bone marrow   CD   Crohn’s disease   CQA   Critical quality attributes   DSA   Donor specific antigens   DSMB   Data and safety monitoring board   EMA   European Medicines Agency   ESRD   End-stage renal disease   FDA   Food and Drug Administration   GMP   Good manufacturing practice   HbA1c   Haemoglobin A1c   HLA   Human leukocyte antigen   ICH   International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use   IDO   Indoleamine 2,3 dioxygenase   IFN-γR1   Interferon gamma receptor 1   IL   Interleukin   ISCT   International Society for Cell and Gene Therapy   LPS   Lipopolysaccharide   MA   Meta-analysis   MOA   Mechanism of action   MS   Multiple sclerosis   MSC   Mesenchymal stromal cell   PDL   Population doubling level   QC   Quality control   SLE   Systemic lupus erythematosus   SoHO   Regulation on Substances of Human Origin   SR   Systematic review   T1D   Type 1 diabetes   UC   Umbilical cord  

摘要： Mesenchymal stromal cells (MSCs) have been employed in clinical trials for their immunomodulatory capabilities, especially in the treatment of autoimmune disorders such as type 1 diabetes. In January (25-26 th ) 2024, the International Society of Cell and Gene Therapy (ISCT) held a two-day workshop entitled “Cell Therapies for Autoimmune Diseases: MSCs from Biology to Clinical Application” in Paris, France. Key opinion leaders in MSC biology, clinical and regulatory backgrounds came together with European, Asian, North and South American delegates to discuss the need for standardisation in the design, conduct and reporting of MSC clinical trials for autoimmune diseases. The authors of this paper emphasise the need to comply with standard guidelines for protocols and reporting of trials, working towards greater transparency and reproducibility of research. Standardisation in reporting of clinical trials using MSCs for autoimmune disorders is essential so that the reader can interpret data correctly and ensure that meta-analyses are generated from comparable datasets, providing meaningful knowledge and guidelines for those working in the field. In this article the key considerations for the effective design and execution of a clinical trial using MSCs for autoimmune disorders, including product characterisation and key manufacturing parameters are discussed. Recommendations are made with respect to minimal criteria for data reporting to move forward the development of MSC therapy and see a successful transition of these drug products to market, thereby addressing a significant unmet clinical need in autoimmunity.

摘要： Bone metastasis, which is associated with adverse outcomes, is a serious health concern for renal cell carcinoma (RCC) patients, especially considering the limited therapeutic options. In this study, we investigated the expression profiling of circRNAs in five primary RCC samples and RCC-bone metastases (Bone Met) using high-throughput screening and identified an upregulated circRNA in Bone Met (hsa_circ_0016459, circKCNK2). Notably, overexpression of circKCNK2 could promote osteoclast differentiation and accelerate the destruction of osteolytic bone metastasis by stimulating IL-11 secretion. Additionally, we observed that RCC with a high circKCNK2 expression could benefit from an anti-IL-11 strategy rather than a denosumab-based therapeutic regimen. At the molecular level, circKCNK2 is competitively bound to EDC4 (a scaffold protein of P-bodies). The interaction between circKCNK2 and EDC4 alpha-helical disrupted the combination of DCP1 and DCP2, which weakened the function of P-bodies and resulted in an increased level of IL-11 mRNA and finally activated STAT-3 signaling in osteoclast precursors (OPs). This axis could be blocked with a mutation of EDC4 alpha-helical. Further experiments revealed that increased circKCNK2 production in bone metastases was attributed to decreasing expression of heterogeneous nuclear ribonucleoprotein U (hnRNPU) under an acidic microenvironment. Our findings suggest that circKCNK2 could have a critical role in linking P-bodies to IL-11/STAT-3 signaling. Developing a secure and effective gene delivery system targeted at circKCNK2 is promising for RCC therapy.

关键词： Neuropathic pain   FXR   HDCA   Intestinal microbiota   Inflammation   Bile acids   BSEP   bile salt export pump   CA   cholic acid   CDCA   chenodeoxycholic acid   CYP7α1   cholesterol 7 alpha hydroxylase   DCA   deoxycholic acid   FGF15   fibroblast growth factor 15   FMT   Fecal microbiota transplantation   FXR   farnesoid X receptor   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   HDCA   hyodeoxycholic acid   IL   interleukin   LCA   lithocholic acid   LC-MS   liquid chromatography-mass spectrometry technique   MMP   matrix metalloproteinase   NLRP3   NOD-like receptor protein-3   OTU   operational taxonomic unit   PCR   polymerase chain reaction   PPAR-γ   peroxisome proliferator-activated receptor gamma   PWL   paw withdraw latency   PWT   paw withdrawal threshold   SNL   spinal nerve ligation   TBA   total bile acid   TCA   taurocholic acid   TCDCA   taurochenodeoxycholic acid   TDCA   taurodeoxycholic acid   TEM   transmission electron microscopy   TGR5   takeda G protein-coupled receptor 5   TLCA   taurolithocholic acid   TNF-α   tumor necrosis factor-alpha   WT   wild-type   ZO-1   zonula occludens-1   α-TMCA   α-tauromuricholic acid   β-TMCA   β-tauromuricholic acid  

摘要： Background Neuropathic pain, is a chronic condition stemming from nervous system injuries. The farnesoid X receptor (FXR), primarily expressed in the liver and intestines, plays a crucial role in regulating bile acids and lipids metabolism. Emerging evidence suggests that bile acids might influence neural function through FXR modulation. Objective To investigate the specific role of intestinal FXR in the modulation of neuropathic pain. Methods A neuropathic pain model was established in mice through ligation of the lumbar 4 spinal nerve (SNL). FXR expression was detected in the distal ileum and spinal cord. The baseline pain threshold and pain-related behaviors were evaluated in FXR gene knockout ( Fxr -/- ) mice. To examine the pharmacological role of FXR activation, obeticholic acid (INT-747, 10 mg/kg/day for 14 days) and HDCA (20 mg/kg/day for 21 days) were administered via intragastric gavage, and changes in pain behaviors were monitored. Additionally, the bile acid profiles of Fxr -/- mice and SNL mice were also analyzed. Furthermore, the effects of FXR on intestinal barrier function, gut microbiota composition, and systemic inflammation regulation were systematically evaluated. Results Neuropathic pain was associated with reduced FXR levels in the gut and spinal cord, accompanied by decreased bile acid levels, especially HDCA. FXR deficiency lowered the pain threshold, whereas treatment with INT-747 or HDCA relieved pain in SNL mice. Activation of FXR restored intestinal barrier integrity, balanced microbiota, reduced inflammation, and decreased microglial activation. HDCA alleviated pain by modulating FXR activity, increasing peroxisome proliferator-activated receptor gamma (PPAR-γ) expression and reducing abnormal matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-2 (MMP-9) activation. Conclusion This research highlights a critical link between FXR levels and neuropathic pain. Manipulating FXR activity with INT-747 or HDCA not only reduced pain

关键词： antigens/peptides/epitopes   genomics   MHC   structural biology/crystallography  

摘要： The major histocompatibility complex (MHC) plays a key role in pathogen recognition as part of the adaptive immune system. MHC I gene copy numbers in birds of the order Passeriformes (songbirds) are substantially larger compared to other birds. MHC I diversity and antigen presentation have been carefully characterised in chicken Gallus gallus of the order Galliformes;chickens express few MHC I genes and often present antigens that bulge out of the peptide binding cleft. This observation raises the question of whether MHC I presents antigens in a similar way in species with many MHC genes? Here, we present the X-ray structure of MHC I from the great reed warbler Acrocephalus arundinaceus (Acar3) a long-distance migratory songbird. Structural analysis shows that MHC I binds the antigen in a flat conformation due to a sequentially well-conserved restriction point, acting like a pair of tweezers, within the peptide binding grove, created by Arg97 and Arg155. This more stringent antigen presentation by Acar MHC I molecules may partly explain the high MHC gene copy numbers seen in the great reed warbler.

关键词： Animal model   Immunodeficient mouse   Humanized mouse   Xenotransplantation   CRISPR/Cas9 system  

摘要： Immunodeficient mouse models are invaluable tools for preclinical research, particularly for cancer therapies and studies of the human immune system. Notably, strains with combined Prkdc (scid) and Il2rg (null) mutations-such as NOG and NSG mice- are widely used due to their profound immunodeficiency, allowing efficient engraftment of various human cells. However, these models were generated by disrupting the Il2rg gene through replacement with a neomycin resistance (Neo) cassette in embryonic stem cells. Incomplete excision of this cassette can inadvertently alter the expression of neighboring genes, thereby introducing potential confounding variables. In addition, they may still express mutant mRNAs that escape nonsense-mediated decay (NMD) and/or produce truncated proteins with residual activity, potentially compromising the interpretation of experimental outcomes. To address this, we developed the N2G mouse strain (NOD-2-Genes KO) where almost all genomic loci of both Prkdc and Il2rg genes are deleted via CRISPR/Cas9 genome editing. N2G mice exhibited tumor growth comparable to NOG mice following the transplantation with several human cancer cell lines. Moreover, human CD34+ cord blood (CB) cells engrafted into N2G mice showed robust reconstitution of human immune cells, especially T cells in peripheral blood, spleen and bone marrow, compared to NSG mice. These results suggest that N2G mice, lacking residual mutant mRNA and the exogenous Neo resistant gene, offer an advanced model for preclinical studies.

关键词： connective tissue disease   IL-18   interstitial lung disease   KL-6   S100A8/A9  

摘要： To investigate the correlation between serum Krebs von den Lungen-6 (KL-6), Interleukin-18 (IL-18), S100A8/A9, and the diagnosis and severity of connective tissue disease-associated interstitial lung disease (CTD-ILD) by detecting the serum expression levels of KL-6, IL-18, and S100A8/A9 in patients with CTD-ILD. Serum samples of healthy controls, CTD patients without ILD, and CTD patients with ILD were collected. Enzyme-linked immunosorbent assay was used to determine serum KL-6, IL-18, and S100A8/A9 expression levels in each group. SPSS 20.0 statistical software was applied to analyze the data. Serum KL-6, IL-18, and S100A8/A9 levels in the CTD-ILD group were higher than those in the CTD and healthy controls groups, and the difference was statistically significant (P < .05). Serum KL-6 levels in the CTD-ILD group were negatively correlated with the lung function indexes (% forced vital capacity [FVC%] and % diffusing capacity of the lungs for carbon monoxide [DLCO%]) (r = -0.413, P = .017;r = -0.402, P = .023), and IL-18 and S100A8/A9 had no significant correlation with FVC% and DLCO% (P > .05). The optimal threshold value of KL-6 for diagnosis of CTD-ILD was 4.73 ng/mL (sensitivity: 89%, specificity: 62.3%, P < .05), and the optimal threshold value of IL-18 for diagnosis of CTD-ILD was 294.07 pg/mL (sensitivity: 87.9%, specificity 83.6%, P < .05), and the optimal critical value of S100A8/A9 for diagnosing CTD-ILD was 303.77 ng/mL (sensitivity: 97%, specificity 70.5%, P < .05). The combined diagnosis of CTD-ILD by serum KL-6, IL-18, and S100A8/A9 had a sensitivity of 87.9% and a specificity of 95.1%, and the combined detection of the 3 markers could improve the diagnostic specificity. Serum KL-6, IL-18, and S100A8/A9 are valuable in the diagnosis of CTD-ILD. They can be used as serologic indicators for diagnosing ILD.

摘要： Tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced hepatocellular carcinoma (HCC). However, their therapeutic efficacy is often limited by drug resistance, primarily driven by tumoral intrinsic mechanisms. In this study, we demonstrate that IFN gamma in the tumor microenvironment can potentiate TKI response, and that ablation of IFN gamma receptor on HCC cells leads to TKI resistance in vivo. Mechanistically, IFN gamma synergizes with TKI to induce GSDME-mediated pyroptosis of HCC cells. The PERK-mediated unfolded protein response (UPR) protects HCC cells from TKI-induced pyroptosis. IFN gamma attenuates PERK activation by inducing the expression of PDIA1, which alleviates the stress of protein unfolding. In vivo, PERK inhibition augments TKI therapy, and elevated PERK expression correlates with poor overall survival of patients with HCC. Moreover, IFN gamma-producing CD8+ T cells can potentiate TKI efficacy. Combining PD-1 blockade to activate T-cell response with TKI therapy synergistically suppresses the growth of GSDME-expressing HCC tumors, which is further enhanced by the PERK inhibitor. Our findings reveal how IFN gamma signaling modulates TKI response and demonstrate the potential of a sequential combination of ICB-mediated immunotherapy and TKI therapy for patients with GSDME+ HCC.T cell-derived IFN gamma enhances TKI-induced pyroptosis in HCC. Mechanistic illustration of IFN gamma secreted from CD8+ T cells enhancing TKI-induced GSDME-mediated pyroptosis in hepatocellular carcinoma via suppression of the PERK pathway. Created with ***.

关键词： Multiple sclerosis   HLA-DRA   HLA-DQA1   IL-6  

摘要： BackgroundMultiple sclerosis (MS), which can lead to severe physical or cognitive disability and neurological deficits, is a chronic autoimmune disease affecting the central nervous system (CNS). The etiology and pathogenesis of MS remain unclear;nonetheless, it is asserted that its cause is complex, with genetic predisposition playing a significant role. In this study, our aim was to analyze the relationship between MS and HLA-DRA (rs3135388 and rs3135391), HLA-DQA1 (rs9272346) and IL-6 (rs1800795 and rs1900796) gene polymorphisms, which play an important role in inflammation and immune *** study included 100 healthy controls and 98 MS patients. Real-time polymerase chain reaction (RT-PCR) was used to analyze variations in rs3135388 and rs3135391 in the HLA-DRA gene, rs9272346 in the HLA-DQA1 gene, and rs1800795 and rs1900796 in the IL-6 gene following DNA isolation from peripheral blood. Statistical techniques were applied to assess the *** results showed a significant difference in IL-6 (rs1800796) G/C (p = 0.024) between the patient and control groups when genotypes and allele distributions were analyzed. HLA-DQA1 (rs9272346) and HLA-DRA (rs3135388 and rs3135391) variations did not substantially differ between the two groups. Similarly, no significant difference was found between the two groups in VitD, B12 and folic acid parameters, and there was no relationship between these parameters and *** is evidence suggesting a significant association between IL-6 (rs1800796) polymorphisms and MS. IL-6 (rs1800796) GC genotype may be associated with disease susceptibility or risk. This should be taken into account in association and intervention studies on MS.