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关键词： BCG revaccination   BCG prime-boost strategy   Adult tuberculosis   Primary Mycobacterium tuberculosis infection   IL-10 inhibition   Memory CD4(+) T cell  

摘要： Background The Bacillus Calmette-Gu & eacute;rin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccine candidates. To effectively control the persistent epidemic of adult TB, it is imperative to investigate the mechanisms responsible for the suboptimal efficacy of the BCG prime-boosting strategy against primary Mycobacterium tuberculosis (***) infection. Methods C57BL/6J mice were immunized with the BCG vaccine either once or twice, followed by analysis of lung tissue to assess changes in cytokine levels. Additionally, varying intervals between vaccinations and detection times were examined to study IL-10 expression across different organs. IL-10-expressing cells in the lungs, spleen, and lymph nodes were analyzed through FACS and intracellular cytokine staining (ICS). BCG-revaccinated IL-10-/- mutant mice were compared with wild-type mice to evaluate antigen-specific IgG antibody and T cell responses. Protection against *** aerosol challenge was evaluated in BCG-revaccinated mice, either untreated or treated with anti-IL-10R monoclonal antibody. Results IL-10 was significantly upregulated in the lungs of BCG-revaccinated mice shortly after the booster immunization. IL-10 expression peaked in the lungs 3-6 weeks post-revaccination and was also detected in lymph nodes and spleen as early as 2 weeks following the booster dose, regardless of the intervals between the prime and booster vaccinations. The primary sources of IL-10 in these tissues were identified as macrophages and dendritic cells. Blocking IL-10 signaling in BCG-revaccinated mice-either by using IL-10-/- mutant mice or administering anti-IL-10R monoclonal antibody increased levels of antigen-specific IFN-gamma+ or IL-2+ CD4+ T cells, enhanced central and effector memory CD4+ T cell responses, and provided be

关键词： IL-15   combination therapy   dose-limiting toxicities   prodrug   resistance   tumor-conditional  

摘要： It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Ra-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-g levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.

关键词： Pemphigus   HLA   cytokine   autoimmunity   Th17   Th2  

摘要： Introduction Cytokines and chemokines direct the inflammatory response and may serve as markers of immune dysregulation in Pemphigus vulgaris (PV), an autoimmune blistering skin disorder. Previous studies on limited numbers of patients and cytokine profiles in PV have produced equivocal results regarding the role these mediators play in *** In this study, we interrogated serum samples from 116 PV patients and 29 healthy controls by multiplexed bead array assays across a comprehensive set of cytokines and chemokines covering several functional categories, including IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, IL-22, IL-23, TNF alpha, IFN gamma, MCP-1, and *** We found that patients with PV generally display an activated cytokine and chemokine immune response compared to controls, but also show remarkable interindividual heterogeneity in terms of cytokine levels, with a limited activation of different T helper cell pathways in different patients. Surprisingly, we also found that healthy individuals that carry the PV susceptibility alleles HLA DR4 (DRB1*0402) and/or DR6 (DQB1*0503) (HLA-matched controls) show an upregulation of cytokine and chemokine levels that are on par with those seen in PV patients for certain pro-inflammatory, Th2, and Th17 mediators and IL-8, while healthy controls that did not carry the PV susceptibility alleles (HLA-unmatched controls) express significantly lower levels of these cytokines and *** Our data suggest the existence of a limited immune activation linked to the presence of key PV associated HLA alleles regardless of disease status. Interestingly, the cytokines IL-10 and IL-15 were found to be significantly downregulated in the HLA-matched control group, suggesting the presence of a possible counter-regulatory function in genetically susceptible but disease-free individuals.

关键词： Chemotherapy   Doxorubicin   Nephrotoxicity   Oxyresveratrol   Dapagliflozin  

摘要： PurposeAmong the most undesirable effects that lead to the restriction of doxorubicin (DOX) use in chemotherapy is kidney damage. This research aimed to assess the possible defenses against DOX-induced nephrotoxicity offered by oxyresveratrol (ORES) and/or dapagliflozin (DAPA).MethodsFive groups of eight male Swiss albino rats each were created from a total of sixty-four. One intravenous injection of DOX (10 mg/kg) was given into the tail vein on the fourteenth day of the experiment;in the meantime, ORES (80 mg/kg) and DAPA (10 mg/kg) were given orally 14 days prior to the DOX injection and 2 days following the DOX *** rats given DOX, ORES and/or DAPA both successfully reduced the kidney weight, kidney/bodyweight ratio, and blood levels of creatinine, uric acid, and urea. They also increased final body weight and albumin serum levels. Additionally, lower serum concentrations of TNF-alpha and IL-6 were noted, along with a lower kidney content of caspase-3. Furthermore, the expression of the Bcl-2 gene was upregulated, as were the Nrf-2, PPAR-gamma, and HO-1 proteins, and there was a downregulation of the ATG-5, Keap-1, and NF-kappa B renal gene expression. These findings support a decrease in oxidative stress and relief of histopathological *** current study's findings suggest that ORES and/or DAPA pretreatment could be a viable therapeutic approach to ameliorate DOX-induced nephrotoxicity.

关键词： interferon   cocktail   African swine fever   viral load   mortality  

摘要： African swine fever (ASF), a highly virulent viral infection, poses a significant threat to the global pig industry. Currently, there are no commercially available vaccines against ASF. While the crucial role of interferon (IFN) in combating viral infections is well-established, its impact on the clinical signs and mortality rates of ASF remains unclear. In this study, swine IFN-alpha 2, IFN-gamma, and IFN-lambda 3 were fused with the Fc segment of immunoglobulin G (IgG) and expressed in mammalian cells (293T), and the antiviral efficacy were detected by VSV-3D4/2 and VSV-PK15 systems. Then, the interferon stimulating genes (ISGs) induced by IFNs-hFc in 3D4/2 cells were determined by qRT-PCR. Also, the preventive potential of the interferon (IFN) cocktail (a mixture of IFN alpha 2-hFc, IFN gamma-hFc, and IFN lambda 3-hFc) were evaluated in vivo by 25-day-old piglets. The results showed that the specific activities of IFN alpha 2-hFc, IFN gamma-hFc, and IFN lambda 3-hFc were 2.46 x 107 IU/mL, 4.54 x 109 IU/mL and 7.54 x 1010 IU/mL, respectively. The IFN-hFc significantly induced the expression of various IFN-stimulated genes (ISGs) in 3D4/2 cells after IFNs-Fc treatment, including IFIT5, Mx1, OASL, ISG12, STAT1, IRF1, PKR, CXCL10, and GBP1. Furthermore, the IFN cocktail treatment reduced the viral load, delayed death, and reduced tissue injury in the piglets infected with ASF virus (ASFV). in conclusion, these results suggest that the IFNs-hFc showed high anti-viral activity, and the IFN cocktail may be potential for the prevention and treatment of ASF.

关键词： Allogeneic hematopoietic cell transplantation   Mesenchymal stromal cells   GVHD   Prevention   HLA mismatch  

摘要： BackgroundMesenchymal stromal cells (MSC) have immunomodulatory and hematopoiesis-supporting properties that could potentially benefit hematopoietic stem cell (HSC) engraftment and decrease the incidence and/or severity of graft-versus-host disease (GVHD).MethodsBased on our previous pilot study, we established a multicenter, prospective, randomized, double-blind trial evaluating the efficacy of co-infusing third-party MSC (1.5-3 x 106/kg) versus placebo on the day of HSC transplantation (HCT) to prevent GVHD in recipients of HLA-mismatched unrelated donors after reduced-intensity *** study planned to include 120 patients to improve 1-year overall survival (OS) from 55 to 77% but was stopped after 9 years for low recruitment (n = 38). One-year OS was 74% in the MSC group and 80% in the placebo group. In multivariate analysis, the incidence of grade II-IV acute GVHD was significantly lower in patients receiving MSC (HR 0.332, 95% CI 0.124-0.890, p = 0.0284). No difference was observed in the incidences of chronic GVHD, infection or relapse, overall or progression-free survival at 1 year or long-term, or hematopoietic and immune *** premature study closure, the suggested beneficial effect of MSC co-transplantation for the prevention of acute GVHD in HLA-mismatched HCT warrants further investigation.

关键词： Distalization   GDA   GLA   HDA   HLA   Lateralization   Reverse Shoulder Arthroplasty   mDSA  

摘要： INTRODUCTION:The focus in reverse shoulder arthroplasty (RSA) has been on the lateralization and distalization of prosthesis positioning, influenced by implant design and surgical technique. There's no consensus on the optimal amount of lateralization and distalization or the best radiographic parameters for evaluating placement. This study examines the correlation and the predictive value between previously described modified distalization shoulder angle (DSA) and lateralization shoulder angle (LSA) with postoperative outcomes, which aim to differentiate the contributions of the humeral and glenoid components in the global distalization and lateralization of the RSA. The LSA was divided into the glenoid lateralization angle (GLA) and the humeral lateralization angle (HLA); the modified distalization shoulder angle (mDSA) was divided into the glenoid distalization angle (GDA) and the humeral distalization angle (HDA). Our hypothesis was that these new angles play a marginal role in predicting clinical outcomes. MATERIALS AND METHODS:Retrospective analysis of 83 RSA patients from 2017-2021 at San Pietro Fatebenefratelli Hospital, Rome. Angles were measured using true anteroposterior radiographs. Clinical outcomes were assessed using the Constant-Murley Score (CS), a visual analogue scale (VAS) for pain, and range of motion (ROM). RESULTS:A weak correlation was found between the modified angles and clinical outcomes. Modified DSA (mDSA) correlated positively with internal rotation and negatively with VAS score. Glenoid distalization angle (GDA) correlated positively with abduction, forward flexion, and CS. Humeral distalization angle (HDA) correlated positively with internal rotation and negatively with VAS. Glenoid lateralization angle (GLA) and humeral lateralization angle (HLA) showed negative correlation with internal rotation and positive correlation with VAS. CONCLUSION:Modified DSA and LSA show marginal correlation with postoperative outcomes and have limited p

摘要： OBJECTIVE:The efficacy of TNF inhibitors for treating chronic low back pain with Modic changes is uncertain. This study investigated the superiority of infliximab over placebo in patients with Modic changes type 1. METHODS:In this multicenter, randomized, triple-blind, placebo-controlled trial, patients aged 18-65 with moderate to severe chronic low back pain and Modic changes type 1 were enrolled from five Norwegian public hospitals between January 2019 and October 2022. Participants were randomly assigned to four intravenous infusions of 5 mg/kg infliximab or placebo. The primary outcome was difference in change in the Oswestry Disability Index (ODI) score from baseline to 5 months. Secondary outcomes included changes in low back pain intensity, disability, and health-related quality of life. A linear mixed model was used for efficacy analyses. RESULTS:128 patients (mean age 43 years, 65.6% women) participated (64 in each group). All patients who received at least one dose of the allocated infusion were included in the primary analyses. The average ODI score change was -7.0 (9.7) in the infliximab group and -6.4 (10.4) in the placebo group. The difference in the ODI change between the two groups was 1.3 ODI points (95% CI, -2.1 to 4.6; p= 0.45). Analyses showed no effect of infliximab compared to placebo on secondary outcomes. Adverse event rates were similar between groups. CONCLUSIONS:Infliximab did not demonstrate superiority over placebo in reducing pain-related disability in patients with moderate to severe chronic low back pain with Modic changes type 1 at 5 months.