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摘要： Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21 macrophages in aged mice. Supernatant collected from p21 macrophage primary culture inhibited the cytotoxic function and proliferation of CD8 T cells. Zfp36 is highly expressed in senescent p21 macrophages. To determine its role in renal allograft rejection, we studied mice with Zfp36 conditionally deleted in macrophages (Zfp36-cKO). These mice developed exacerbated allograft rejection with enhanced IL-27 production and CD8 T cell hyperactivation. Inhibition of IL-27 with neutralizing antibody or deletion of IL-27 receptor on CD8 T cells reversed acute renal allograft rejection in Zfp36-cKO mice. Moreover, in vitro silencing Zfp36 with siRNA led to impaired degradation of IL-27 p28 mRNA and a subsequent increase of IL-27 in p21 macrophages. In conclusion, senescent macrophages protect renal allograft rejection by suppressing CD8 T cells via a Zfp36/IL-27-dependent mechanism. These findings may provide innovative therapeutic strategies for addressing kidney allograft rejection.

摘要： Glaucoma is a group of neurodegenerative eye diseases characterized by progressive damage to the optic nerve which is typically asymptomatic until irreversible vision loss has occurred. Early screening is essential for timely treatment to prevent visual impairment. However, existing detection methods struggle to achieve a balance between accuracy, time efficiency, and portability. The lateral flow assay (LFA) is a well-established immunoanalytical tool for point-of-care (POC) analysis. Here, we have developed a unique dual-testing, quantum nanobeads-based fluorescence LFA, allowing for the simultaneous and quantitative detection of two glaucoma biomarkers: tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF). By coating quantum dots on the surface of a SiO core, the fluorescent intensity of the quantum nanobeads was enhanced enabling an accurate, efficient, and high-throughput bioanalytical performance, with low detection limits of 3.39 pg mL for TNF-α and 4.13 pg mL for BDNF. The LFA also demonstrated superior selectivity, reproducibility, and stability to the standard enzyme-linked immunosorbent assay (ELISA). Using a 3D-printed readout box, the analysis of the LFA requires only a readily accessible smartphone and image processing software, making it an ideal POC detection tool. This ultrasensitive, economical, and user-friendly LFA demonstrates significant potential as an alternative for glaucoma screening.

关键词： Aqueous humor   interleukin-6   pentraxin 3   uveitis  

摘要： PURPOSE:Evidence exists that pentraxin 3 (PTX3) is involved in the pathogenesis of autoimmune diseases. The aim of this study was to analyze the levels of PTX3 in aqueous humor (AH) samples from patients with specific autoimmune uveitic entities. In addition, we correlated PTX3 levels with the levels of proinflammatory cytokines and chemokines and the clinical disease activity. METHODS:AH samples from patients with active uveitis associated with human leukocyte antigen (HLA)-B27-related inflammation ( = 12), Behçet's disease (BD) ( = 13), Vogt-Koyanagi-Harada (VKH) disease ( = 12), sarcoidosis ( = 8) and control subjects ( = 9) were measured with the use of multiplex assays. RESULTS:When considering all uveitis patients as one group ( = 45), PTX3 levels were significantly increased compared to controls ( = 0.002). When comparing the four individual disease groups to controls, PTX3 levels were significantly higher in only HLA-B27-associated uveitis ( < 0.001). PTX3 levels were significantly higher in patients with HLA-B27-associated uveitis than in patients with BD ( = 0.034) and VKH disease ( < 0.001). PTX3 levels had a significant correlation with clinical disease activity ( = 0.480;  = 0.001) and strong positive correlations with aqueous humor levels of interferon-γ ( = 0.749;  < 0.001), interleukin (IL)-1ß ( = 0.804;  < 0.001), IL-6 ( = 707;  < 0.001), CCL20 ( = 0.691; < 0.001) and CXCL8 ( = 0.775;  < 0.001). CONCLUSIONS:PTX3 is an inflammatory marker and might exert a pathogenic role in HLA-B27-associated uveitis.

关键词： Antimetabolites   TNF inhibitor   immunosuppression   uveitis  

摘要： PURPOSE:To compare the corticosteroid sparing efficacy of frequently used antimetabolites to tumor necrosis factor (TNF) inhibitors in the management of noninfectious ocular inflammation. METHODS:Retrospective analysis of patients with noninfectious uveitis on conventional antimetabolite (methotrexate, mycophenolate mofetil, azathioprine,or leflunomide, "CONV") or a TNF inhibitor (adalimumab or infliximab, "TNFi") with active inflammation or more than 7.5 mg daily prednisone. Eyes were assessed in three groups: CONV only, TNFi only and combination of both (COMB). Cox regression models compared treatment success, adjusted for age, race, smoking, anatomic location of uveitis, duration of uveitis and visual acuity. Corticosteroid sparing success was defined as: inactive or slightly active uveitis on <=7.5 mg daily oral prednisone and <=2 drops of prednisolone acetate 1%. RESULTS:There were 1475 eligible patients in the analysis. By 6 and 12 months, respectively, the Cox model-predicted, percentage success was 27.6% and 44.9% for the CONV group; 34.2% and 53.9% in the TNFi group and 39.9% and 61.1% for the COMB group. COMB was more likely than CONV to achieve success (adjusted HR 1.58 (95% confidence interval (CI), 1.28, 1.95, < 0.0001). Factors associated with lower success were age under 18 years, smoking, visual acuity worse than 20/50 at cohort entry, over 4-year duration of uveitis and daily baseline prednisone 7.5 mg or higher (all < 0.05). CONCLUSION:Our results suggest COMB is more effective than CONV at achieving disease quiescence and corticosteroid sparing success among patients with active noninfectious uveitis. More research is needed to determine if TNFi alone is superior to CONV for uveitic corticosteroid-sparing.

关键词： Cellular immune response   Genetic diseases   Genetics   Immunology  

关键词： ECs pyroptosis   DR   circTHADA   CASP1   ceRNA network  

摘要： Our study aimed to elucidate the mechanism by which circTHADA competitively adsorbs miR-494-3p to regulate CASP1-mediated endothelial cell (EC) pyroptosis in diabetic retinopathy (DR). To be specific, we used high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs) as DR cell models and streptozotocin (STZ)-treated mice as DR mouse models. The expression levels of circTHADA, miR-494-3p, CASP1, NLRP3, GSDMD-N and IL-1 beta were detected and flow cytrometry was applied to measure cell pyroptosis rate and dual luciferase reporter assays were utilized to determine the direct binding sites. As a result, exacerbated EC pyroptosis in DR was detected in DR cell and mouse models. Based on differentially expressed circRNA profiles by microarray and experimental verification, circTHADA was filtered and identified to regulate CASP1-mediated EC pyroptosis. miR-494-3p was then proven to be involved in circTHADA-mediated ceRNA network by bioinformatics analysis and experimental verification. Further gain- and loss-of-function experiments and rescue experiments revealed the function of the circTHADA/miR-494-3p/CASP1 axis in pyroptosis.

关键词： Acute respiratory distress syndrome   COVID-19   Interleukin-6   Randomized controlled trial   Tocilizumab   Viral pneumonia  

摘要： BACKGROUND:The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia. TRIAL DESIGN:Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL. METHODS:Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed. RESULTS:Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC. CONCLUSION:Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.

关键词： Immunology   Immunotherapy   NKT cells   Oncology  

摘要： Pancreatic ductal adenocarcinoma cancer (PDAC) continues to pose a significant health burden, with a 5-year survival rate of only 10%. Prostate stem cell antigen (PSCA) is highly expressed on the surface of tumor cells of most PDAC patients, with minimum expression in most normal tissues. Here, we generated cryopreserved, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) invariant NKT (iNKT) cells using human peripheral blood mononuclear cells as a cell source. In multiple in vitro and in vivo PDAC models, freshly manufactured PSCA CAR_sIL-15 iNKT cells and frozen-thawed, off-the-shelf PSCA CAR_sIL-15 iNKT cells demonstrate comparable efficacies, and both show remarkable suppression of PSCA-positive and gemcitabine-resistant PDAC. Importantly, off-the-shelf cryopreserved PSCA CAR_sIL-15 iNKT cells show equivalent efficacy when compared with PSCA CAR T cells using the same PSCA CAR and in the same PDAC model; however, PSCA CAR_sIL-15 iNKT cells do not appear to induce systemic toxicity or graft-versus-host disease, thus allowing for multiple infusions to control recurrent disease. Collectively, our study suggests that PSCA CAR_sIL-15 iNKT cells merit clinical investigation for PDAC patients exhibiting positive PSCA expression. The therapy could be given as a single agent or in combination with established therapeutic modalities for PDAC.

关键词： Gut microbiota   Interleukin- 22   Intestinal barrier   Obesity-related hypertension   Sympathetic nerve  

摘要： BACKGROUND:Gut microbiota and its metabolites, as well as the intestinal barrier, play important roles in the development of obesity-related hypertension. Sympathetic nerves are critical for intestinal homeostasis. Carotid baroreceptor stimulation (CBS) has been shown to exert protective effects against hypertension via sympathetic tone reduction. This study aimed to reveal the effects of CBS treatment on intestinal homeostasis and its underlying mechanisms in obesity-related hypertension. METHODS:An animal model of obesity-related hypertension was established with Sprague-Dawley rats by a high-fat diet and 10% fructose solution for 13 weeks. CBS devices were implanted at the 5 th week. The effects of CBS on body weight, blood pressure, gut microbiota, intestinal autonomic nerve, intestinal barrier, and type 3 innate lymphoid cells (ILC3 s) were investigated. RESULTS:CBS treatment significantly reduced blood pressure and body weight in rats with obesity-related hypertension. In addition, CBS obviously improved gut microbial dysbiosis and intestinal barrier damage. Interestingly, after an 8-week CBS intervention, the obesity-related hypertensive rats exhibited a dramatic decrease in sympathetic nerve distribution and norepinephrine concentration, as well as an increase in IL- 22 production by ILC3 s in the intestine. CONCLUSIONS:CBS increased IL- 22 production in ILC3 s to alleviate gut microbial dysbiosis and intestinal barrier destruction, thus improving obesity-related hypertension in rats.