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关键词： pluripotent   phagocytosis   sphingosine-1-phosphate   HLA   immunotolerance   clinical trials  

摘要： Muse cells are endogenous reparative stem cells with dual characteristics: pluripotent-like and macrophage-like. They can be identified by the pluripotent surface marker stage-specific embryonic antigen-3-positive (SSEA-3 (+)) cells in the bone marrow, peripheral blood, and various organs, including the umbilical cord and amnion. Muse cells can differentiate into ectodermal, endodermal, and mesodermal lineage cells, self-renew, and selectively migrate to damaged sites by sensing one of the universal tissue damage signals, sphingosine-1-phosphate (S1P). At these sites, they phagocytose damaged/apoptotic cells and differentiate into the same cell type as the phagocytosed cells. In this manner, Muse cells replace damaged/apoptotic cells with healthy, functioning cells, thereby repairing tissues. Due to their specific immunosuppressive and immunotolerant mechanism, clinical trials have been conducted for acute myocardial infarction (AMI), subacute ischemic stroke, epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), cervical spinal cord injury, neonatal hypoxic-ischemic encephalopathy (HIE), and COVID-19 acute respiratory distress syndrome. These trials involved the intravenous injection of similar to 1.5 x 107 donor Muse cells without human leukocyte antigen (HLA) matching or immunosuppressant treatment, and they demonstrated safety and therapeutic efficacy. Thus, donor Muse cell treatment does not require gene manipulation, differentiation induction, or surgical intervention. These unique characteristics distinguish Muse cells from other somatic stem cells, such as mesenchymal stem cells, VSEL stem cells, and marrow-isolated adult multi-lineage inducible (MIAMI) cells.

关键词： Peronema canescens Jack.   kaempferol   IL-6   molecular docking   molecular dynamics   RAW 264.7  

摘要： Sungkai leaves were selected due to their herbal medicine prevalence and documented biological activities. This study explores the immunomodulatory potential of kaempferol isolated from Sungkai (Peronema canescens Jack.) through a combination of in silico and in vitro methods. P. canescens leaves were extracted with ethanol using maceration, followed by fractionation with n-hexane, ethyl acetate, and water using a separatory funnel. Among all the fractions, the ethyl acetate fraction demonstrated the strongest inhibitory effect on IL-6 (Interleukin 6) expression, leading to further separation for the enhanced analysis of its activity. The resulting sub-fractions were purified by vacuum liquid chromatography with n-hexane and ethyl acetate gradient. Sub-fraction E was isolated through preparative thin-layer chromatography to obtain a pure compound identified as kaempferol using UV, FTIR, MS, and NMR analyses. The isolated kaempferol was then evaluated by molecular docking and molecular dynamics simulations, employing MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) for binding affinity calculations. Kaempferol showed a binding affinity (Delta G) of -5.98 kcal/mol, slightly stronger than TLA (tartaric acid) (-5.90 kcal/mol). Key interactions with amino acid residues, such as Gln175, Arg182, and Arg179, were observed. Additionally, molecular dynamics simulation demonstrated that kaempferol exhibited better stability than TLA between 15 ns and 100 ns. The MM-PBSA analysis showed that kaempferol has strong van der Waals (-17.02 kcal/mol) and electrostatic interactions (-293.16 kcal/mol), with binding free energy (-17.85 kcal/mol) significantly stronger than TLA (-1.00 kcal/mol). This stability, combined with its ability to reduce IL-6 expression in vitro, highlights kaempferol's immunomodulatory potential.

关键词： inflammation   senescence   nucleus pulposus cell   intervertebral disc degeneration   homoplantaginin  

摘要： The incidence of intervertebral disc degeneration (IDD) is increasing year by year, while the age of onset of IDD is decreasing year by year. For the individuals affected by IDD, an alternative treatment to surgery is required. IDD is thought to be related to nucleus pulposus (NP) cell senescence and inflammation. Therefore, inhibition of NP cell inflammation and senescence may counteract IDD. We screened 20 small-molecule drugs to compare their anti-inflammatory effects, and finally selected homoplantaginin (HPG) as a treatment regimen. HPG is an extract of Salvia miltiorrhiza with anti-inflammatory properties. The objective of this research was to investigate if HPG could have a therapeutic effect on IDD through its anti-inflammatory or anti-aging effects. We identified the appropriate concentration of HPG in primary NP cell cultures and demonstrated that it inhibited inflammatory pathway activation and reduced the senescence phenotype of NP cells in vitro. And in vivo, the therapeutic effect of HPG on caudal disc degeneration was confirmed consistently. In conclusion, our findings suggest that HPG can alleviate the degeneration in the pathogenesis of IDD and that it has a potential effect in the treatment of IDD.

关键词： IL-33   ST2   macrophage polarization   non-small cell lung cancer   tumor microenvironment  

摘要： Objective: Suppression of tumorigenicity 2 (ST2), the receptor for interleukin (IL)-33, has a critical role in tumor growth, angiogenesis, metastasis, and immune modulation. The IL-33/ST2 pathway is known to influence the polarization and function of macrophages, which is integral to modulating the tumor microenvironment. However, the precise role of IL-33/ST2 in tumors, particularly non-small cell lung cancer (NSCLC), has not been established. Methods: ST2 expression in NSCLC was analysed using a murine model and patient specimens. The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined. Results: Elevated ST2 expression was correlated with aggressive tumor growth. Specifically, ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth. IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/ Akt signalling pathway. Moreover, IL-33 inhibited T-cell function by inducing the secretion of transforming growth factor beta from alternatively activated macrophages. Conclusions: Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy, highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.

摘要： Background:Canine and human malignant melanoma are naturally occurring cancers with many similarities, making the dog an important parallel patient population to study both diseases. However, development of canine anti-human antibodies (CAHA) needs to be considered when evaluating humanized biotherapeutics in dogs. Objectives:Characterize CAHA in sera from dogs with spontaneous melanoma receiving radiotherapy and intratumoral immunocytokine (IT-IC) with humanized 14.18-IL2. Methods:Serum samples were obtained pre-treatment and at several post-treatment times from 12 dogs with locally advanced or metastatic melanoma treated with radiotherapy to the primary site and regional lymph nodes (when clinically involved) followed by IT-IC of humanized 14.18-IL2. Two CAHA assays were developed. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to detect antibodies against the humanized IgG component of hu14.18-IL2. A flow cytometry assay was developed to determine the ability of CAHA to inhibit binding of a mouse anti-GD2 monoclonal antibody to its target. Results:Post-treatment sera from 7 of 12 dogs developed CAHA levels over pre-treatment that were identified by ELISA as significant increases at Day 30 and/or Day 60. Day 10, Day 30, and Day 60 post-treatment sera from 10 of 12 dogs significantly inhibited the binding of anti-GD2 monoclonal antibody to its target compared to pre-treatment. Significant binding inhibition was also detected in 2 of 12 dogs after local RT but before IT-IC (Day 1). Normal canine sera did not mediate binding inhibition. Conclusions:This study advances CAHA detection strategies and reports the kinetics of CAHA following IT-IC in dogs with spontaneous melanoma.

关键词： Adalimumab   Biosimilar   CT-P17   Interchangeability   Psoriasis   Switching   TNF   Tumor necrosis factor inhibitor   Yuflyma (R)  

摘要： Introduction: A 27-week analysis of this phase 3 study demonstrated the interchangeability of the adalimumab biosimilar CT-P17 and reference adalimumab. The current 52-week analysis reports secondary data from the open-label extension period (OLE) of the study. Methods: In this randomized, double-blind, active-controlled phase 3 study, adults with moderate-to-severe chronic plaque psoriasis received (via prefilled syringe) 80 mg subcutaneous reference adalimumab on day 1, then 40 mg 1 week later, and every other week (EOW) until week 11. At week 13, patients were randomized (1:1) to continue reference adalimumab ("continuous" group) or undergo repeated switching between CT-P17 and reference adalimumab ("switching" group) until week 25. Thereafter, patients entered an OLE and received 40 mg CT-P17 EOW from week 27 to 49, with an end-of-study visit at week 52. Here we present findings from the OLE. Pharmacokinetics (PK), efficacy (including mean percent improvement from baseline in Psoriasis Area Severity Index [PASI] score), safety, and immunogenicity were evaluated. Post hoc subgroup analyses were also conducted. Results: Of 327 patients who initiated the OLE, 152 and 160 patients from the switching group and continuous group, respectively, completed the study. Mean serum concentrations were similar between groups throughout the OLE. Efficacy improvements observed up to week 27 were maintained during the OLE and were comparable between groups. At week 52, overall mean (standard deviation [SD]) improvement from baseline in PASI score was 90.34% (16.59). Safety profiles were similar between groups, and immunogenicity did not increase during the OLE. The mean (SD) percent improvement from baseline in PASI score was slightly lower in patients who were antidrug antibody (ADA)-positive versus those who were ADA-negative (89.57 [17.27] versus 97.29 [4.08]) at week 52. Conclusions: PK, efficacy, safety, and immunogenicity findings remained consistent throughout the OLE, reg

关键词： RWE comparison   Ulcerative colitis   anti-TNF   real-world evidence (RWE)   ustekinumab   vedolizumab  

摘要： BACKGROUND:Real-world evidence (RWE) studies of ustekinumab (UST) in ulcerative colitis (UC) are needed because randomized controlled trials do not represent unselected patient populations in everyday clinical practice. Patients with UC were recruited when starting biologic therapy for the first time or switching to a new biologic therapy. This study assessed the effectiveness of maintenance therapy with UST in comparison to anti-TNF or vedolizumab (VDZ) at 12 months. METHODS:Between 2020-2022, 507 UC patients starting biologic therapy for the first time or switching to a new biologic therapy were enrolled at 34 IBD-specialized centres in Germany. After excluding patients receiving other biologics or small molecules, as well as those with stomas or missing outcomes, the final sample consisted of 476 patients. The outcomes were clinical response, clinical remission (CR), and steroid-free remission. Propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was used to reduce the effect of confounding due to physician selection of therapy. RESULTS:A total of 476 patients with UC were included in the analysis (UST: 147, anti-TNF: 168, VDZ: 161). Treatment persistence over 12 months differed significantly (p < 0.001) between UST (93.9%), VDZ (87.0%), and anti-TNF (75.0%). The PS-weighted effectiveness of UST in the mITT analysis at month 12 was not significantly different to anti-TNF or VDZ (CR: UST 26.9%, anti-TNF 34.7%, VDZ 40.9%; p=0.063). CONCLUSION:In the prospective RUN-UC study with PS-weighted groups, UST showed higher treatment persistence but no significant difference in maintenance effectiveness compared to anti-TNF or VDZ in UC.

关键词： MHC class I   antigen presentation   antigen processing   endoplasmic reticulum aminopeptidase   ovalbumin   peptide trimming  

摘要： Peptide presentation by major histocompatibility complex (MHC) class I molecules enables CD8+ T lymphocytes to monitor the intracellular proteome of tissue cells. CD8+ T cell priming and acquisition of effector functions is affected by cognate peptide-MHC-I complex density on the cell surface, which partly depends on the efficacy of intracellular proteolytic peptide generation. Peptide generation frequently requires final trimming by the human aminopeptidases ERAP1, ERAP2, and IRAP. All display genetic polymorphism associated with the risk of multiple autoimmune diseases but also some cancers. This finding has prompted interest in the development of small molecule inhibitors to enhance antitumor or conversely attenuate autoreactive T cell responses. However, efficient assays for assessment of inhibitor effects are wanting. We describe the development of an assay for quantitative assessment by flow cytometry of selective inhibitor effects on peptide trimming both in the endogenous MHC-I processing pathway and in cross-presentation. We use the assay to identify a selective ERAP2 inhibitor and show that inhibitor effects can be read out not only through assessing a specific peptide-MHC complexes but also by measuring cell surface levels of bulk MHC-I molecules. Next to its practical interest as tool for inhibitor testing, our assay highlights how ERAP1-dependent immunodominance of a single epitope processed with exceptional efficacy can have a massive effect on the immunopeptidomic identity of cells presented to CD8+ T cells. We propose that ERAP effects on the presentation of such rare and exceptionally immunodominant epitopes may underlie the epistatic genetic associations of ERAP polymorphism with HLA class I-linked autoimmune diseases.

关键词： SARS-CoV-2   Severe acute respiratory syndrome coronavirus   CAA   Cerebral amyloid angiopathy   LATE-NC   limbic predominant age-related   TDP-43   encephalopathy-neuropathologic changes   AD   Alzheimer’s Disease   IgG   Immunoglobulin G   ANNA-1   type-1 antineuronal nuclear antibody   IFN   Interferon   IL   Interleukin   IL-1RA   Interleukin-1 Receptor Antagonist   IP-10   Interferon gamma-induced protein 10   MCP-1   Monocyte Chemoattractant Protein-1   MIP-1α   Macrophage Inflammatory Protein-1 alpha   TNFα   Tumor Necrosis Factor alpha   VEGF   Vascular Endothelial Growth Factor   RANTES   Regulated upon Activation, Normal T cell Expressed and Secreted  

摘要： BACKGROUND AND OBJECTIVES:A spectrum of neurologic complications associated with COVID-19 are well documented. While neuroinflammation in the brain of COVID-19 patients likely contributes to these complications, the mechanisms of neuroinflammation and correlates of neurologic complications remain elusive, especially since the etiologic pathogen of COVID-19, SARS-CoV-2, minimally invades the CNS. This study aimed to evaluate markers of neuroinflammation, IgG glycosylation patterns indicative of pro- or anti-inflammatory state, and prevalence of brain auto-reactive antibodies in the CSF of COVID-19 patients and their relationship to brain neuropathology. METHODS:We evaluated the CSF of 11 deceased unvaccinated COVID-19 donors and 13 matched non-COVID-19 controls. Markers of neuroinflammation, IgG glycosylation patterns, and brain auto-reactive antibodies were assessed, along with their correlation to brain neuropathology. Statistical analyses were performed to compare groups and assess relationships between variables, using non-parametric tests and bootstrap analysis. RESULTS:COVID-19 CSF showed higher levels of neopterin and ANNA-1, markers of neuroinflammation and autoimmunity, respectively, and lower IFN response compared to non-COVID-19 donors. In brain regions of high microglial activation, IL4 and RANTES were significantly increased. SARS-CoV-2 was undetectable in the CSF and brain of COVID-19 donors, yet anti-SARS-CoV-2 CSF antibodies were detected. Fucosylated IgG were associated with Spike IgG, CSF protein, and soluble CD14, whereas afucosylated bisecting IgG were inversely correlated with Spike IgG. Sialic acid containing IgG were positively correlated with IL1β and TNFα. These associations were not found in non-COVID-19 donors. Inflammatory agalactosylated fucosylated IgG (G0F) were associated with infiltrating CD4 + T cells in the brains of COVID-19 donors. COVID-19 donor CSF displayed higher levels of auto-reactive antibodies to human brain antigens compa