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关键词： Asthma   Anti-IL-5   Anti-IL5R   ACQ5  

摘要： In recent years, the use of monoclonal antibodies directed against interleukin-5 (anti-IL-5) and its receptor alpha (anti-IL-5R) has proven to be an effective therapeutic option for patients with severe asthma by reducing the number of eosinophils, which may promote disease remission. This study aimed to evaluate clinical improvement and remission in patients with severe asthma treated with anti-IL-5 and anti-IL-5R antibodies over a period of 12 months. A cohort study was conducted with 49 patients diagnosed with severe eosinophilic asthma and who did not respond to conventional treatment. During follow-up, medical control was performed every 3 months using spirometry, eosinophil counts, quality of life scales, and disease control. The results revealed an improvement in FEV1 after 3 months of treatment, with statistical significance at 12 months in patients treated with anti-IL-5 and at 9 months in those treated with anti-IL-5R. In addition, better perceptions of asthma control and quality of life were observed, with significant differences at 6 and 12 months. Correlations between spirometry and ACT, ACQ, and AQLQ reflect a progressive recovery of well-being and function. Finally, the remission rate was 41.1% with anti-IL-5 treatment and 47.3% with anti-IL-5R treatment after one year of follow-up. These findings support the efficacy of anti-IL-5 and anti-IL-5R treatment in improving severe asthma control and patients' quality of life, suggesting their key role in disease remission.

关键词： cerebral malaria   GTPases   olfactory bulb   Gbp4   Irgb6  

摘要： Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. Although much progress has been made in understanding CM, the precise pathogenesis remains elusive. The olfactory bulb (OB) has emerged as a critical site of immunopathology in experimental cerebral malaria (ECM) models, but its contribution to disease progression is not fully understood. To investigate the molecular mechanisms driving early ECM pathogenesis, we conducted transcriptomic profiling of the OB to identify key genes associated with disease onset. Our analysis revealed significant early upregulation of interferon (IFN)-inducible GTPases, particularly Irgb6 and Gbp4, effectors downstream of IFN-gamma but not IFN-alpha/beta signaling, suggesting their involvement in ECM pathology. Using Gbp4-/-, Irgb6-/-, and double knockout (Irgb6-/- Gbp4-/-) mice, we identified a pathological role for these GTPases. Mechanistically, we found that double-knockout mice exhibited increased infiltration of CD4+ and CD8+ T cells into the brain but with reduced T cell functionality and impaired antigen presentation by endothelial cells, leading to enhanced parasite accumulation in the OB. This disruption in immune regulation ultimately conferred improved survival in the Irgb6-/- Gbp4-/- mice and indicated the pathological impact of Gbp4 and Irgb6 in ECM. These findings reveal that Gbp4 and Irgb6 play important roles in the early immunopathogenesis of ECM by modulating antigen processing and presentation in the OB, thereby shaping immune cell dynamics. Our work shows the dual role of Irgb6 and Gbp4 GTPases in host defence and immunopathology and offers new insights into ECM mechanisms and antigen *** malaria (CM) arises from an excessive inflammatory response and blood-brain-barrier (BBB) dysfunction in Plasmodium-infected hosts, but the precise mechanisms driving early-stage pathogenesis remain unclear. Through RNA sequencing of the olfactory bulb (OB)

关键词： Vitiligo   Aryl Hydrocarbon Receptor   IFN-γ signalling   Immune checkpoints   Kynurenine pathway  

摘要： The kynurenine (Kyn)-aryl-hydrocarbon-receptor (AhR) axis restrains cytotoxic T-cell activity by tempering IFN-γ release and sustaining immune-checkpoint expression, yet its status in vitiligo remains undefined. We profiled AhR expression in circulating T cells, quantified serum tryptophan (Trp) and Kyn, and assessed intracellular IFN-γ/IL-17A with soluble checkpoint molecules in 186 non-segmental vitiligo patients and 56 matched controls. Vitiligo patients showed significantly reduced AhR expression in CD8 + T cells (p=0.003) and higher Kyn/Trp ratio in active versus stable disease (p=0.048). Low AhR expression in CD8 + T cells correlated inversely with IFN-γ-producing CD8 + cells (r=–0.376; p<0.001), this correlation being stronger in active disease (r=–0.561). AhR expression positively correlated with sBTLA, sPD-1, and sTIM-3 levels in PBMC supernatants from vitiligo patients. Pharmacological activation of AhR with tapinarof dose-dependently suppressed IFN-γ + T-cell frequencies, achieving 55% reduction at 1 μM and 47% reduction at 3 μM compared to stimulated controls (p < 0.05). These data identify disrupted Kyn–AhR signaling as a driver of enhanced IFN-γ production in vitiligo and point to the potential of AhR agonists as targeted therapies to restore immune homeostasis and prevent disease activity in vitiligo.

关键词： Synthesis   TNF-α   TxA2   and IL-6   anti-inflammatory   cytokine   prostaglandin   pyridazine   pyridazinone  

摘要： Inflammation is a fundamental biological reaction to harmful stimuli, which is crucial in the initiation and advancement of different diseases, including rheumatoid arthritis, cardiovascular conditions, neurological disorders such as Alzheimer's and Parkinson's, and multiple cancer types. Chronic inflammation, in particular, contributes to irreversible tissue damage and the progression of disease. Thus, the suppression of key inflammatory mediators has become a promising therapeutic approach. Thromboxane A2 (TxA2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are among the mediators that have been thoroughly investigated for their roles in regulating immune responses and sustaining inflammation; therefore, targeting these mediators offers substantial therapeutic potential. In recent years, significant attention has been focused on heterocyclic compounds, especially pyridazine and pyridazinone derivatives, owing to their structural diversity and extensive biological activity. These scaffolds have shown significant effectiveness in regulating inflammatory pathways by limiting TxA2 production, reducing TNF-α release, and disrupting IL-6 signaling. This review presents a comprehensive overview of pyridazine and pyridazinone-based compounds as potential anti-inflammatory agents. It highlights both traditional and current synthetic strategies used in their development and explores their mechanisms of action with respect to key inflammatory targets. Additionally, the study examines recent pharmacological assessments and preclinical results, offering insights into the medicinal uses of these substances. A brief perspective on future research directions is also included, emphasizing the need for further structural optimization, in vivo validation, and clinical translation. Collectively, these results highlight the potential of pyridazine and pyridazinone derivatives in the development of advanced anti-inflammatory pharmaceuticals.

关键词： Epitope prediction   Epitope presentation   Helper T cells   SARS-CoV-2   Spike protein  

摘要： Early in the COVID-19 pandemic, multiple studies used prediction methods to identify candidate peptides to be included in prospective vaccines. While subsequent studies identified epitopes from convalescent and vaccinated subjects, few studies have compared the predicted to identified epitopes. Here we used three methods to predict SARS-CoV-2 spike protein helper T cell epitopes and compared the results to experimentally determined peptide binding as well as published epitopes. The correspondence between the predicted and experimental binding results and published epitopes depended more on the HLA being investigated than the prediction method used. Lastly, these observations were used to predict peptides which bind to the most HLAs. These peptides were previously identified and predicted to maintain HLA binding in the current variants of interest. This study highlights which prediction methods and conditions lead to the most reliable prediction results which would be of great interest for improving the design of future vaccines.

关键词： chronic antibody-mediated rejection (AMR)   donor-specific antibodies (DSA)   graft fibrosis   immunosuppression   operational tolerance  

摘要： Pediatric liver transplantation, while life-saving, poses long-term challenges in immunosuppression (IS) management. We retrospectively studied 26 pediatric recipients who underwent living donor liver transplantation between 1990 and 1994 and retained their original grafts for over 30 years. Based on IS status at the final follow-up, patients were categorized as IS-free (n=8), IS-resumption (n=9), or IS-continued (n=9). We analyzed liver allograft fibrosis score (LAFSc, range 0-9), donor-specific antibodies (DSA), and liver function tests. At the last follow-up, liver function tests showed no significant differences across groups. The IS-free group had a median IS cessation period of 22.8 years (range: 14.2-26.7) and demonstrated minimal fibrosis (median LAFSc=1) and low DSA prevalence, suggesting potential operational tolerance. The IS-resumption group resumed IS after a median cessation period of 7.9 years (range: 1.3-15.7) due to fibrosis progression and exhibited the highest fibrosis burden (median LAFSc=4) and frequent DSA positivity. Notably, some patients showed a tendency for fibrosis progression despite the restart of IS, suggesting possible subclinical antibody-mediated injury. The IS-continued group experienced fluctuating fibrosis (median LAFSc=1) and multiple late-onset T cell-mediated rejection episodes. Across all groups, high DSA positivity (mean fluorescence intensity >20,000) significantly correlated with advanced fibrosis. In conclusion, the IS-free group's favorable histology and antibody profile support the possibility of durable immune tolerance. Conversely, persistent fibrosis in the IS-resumption group highlights the limitations of conventional IS strategies. Serial histological evaluations and antibody monitoring would be helpful for long-term IS management in pediatric liver transplant recipients.

关键词： HLA novel allele   HLA-E*01:154   nanopore sequencing   PolyseqOne sequencing  

摘要： HLA-E*01:154 differs from HLA-E*01:01:01:01 by a single nonsynonymous nucleotide substitution in codon 199 of exon 3.

关键词： 牦牛犊牛   燕麦干草   苜蓿干草   肠道免疫   细胞因子   转录组学  

摘要： 本试验基于转录组学分析不同粗饲料来源(苜蓿干草、燕麦干草及二者混合干草)饲粮对哺乳期牦牛犊牛肠道免疫功能的影响。选取45日龄、体重(36.47±0.99) kg的健康公牦牛犊牛21头,采用单因素试验设计,随机分为3组(每组7头牛):苜蓿干草组(AH组)、燕麦干草组(OH组)和混合干草组(AO组,苜蓿干草∶燕麦干草=1∶1)。每组犊牛代乳粉、精料和干草饲喂量一致,精粗比为3∶7。当固体干物质采食量达到1 kg/d时,每组选5头犊牛进行屠宰,采集空肠、结肠组织进行转录组学测序与分析。预试期21 d,正试期120 d。结果表明:1)空肠转录分析显示,AH组vs AO组共有1 003个差异表达基因(DEGs),AH组vs OH组共有1 553个DEGs,AO组vs OH组共有919个DEGs。GO富集分析表明,AH组vs OH组的DEGs共注释到680条GO条目,AH组vs AO组的DEGs共注释到646条GO条目,AO组vs OH组的DEGs共注释到606条GO条目。KEGG富集分析显示,AO组主要通过激活补体和凝血级联通路及抗原处理与呈递,进而增强了空肠的免疫功能。2)结肠转录分析显示,AH组vs AO组共有3 362个DEGs,AH组vs OH组共有1 299个DEGs,AO组vs OH组共有1 297个DEGs。GO富集分析表明,AH组vs OH组的DEGs共注释到665条GO条目,AH组vs AO组的DEGs共注释到869条GO条目,AO组vs OH组的DEGs共注释到695条GO条目。KEGG富集分析显示,AO组主要通过激活趋化因子信号通路和紧密连接,进而增强了结肠的免疫功能。综上所述,饲喂混合干草促进了空肠和结肠中免疫相关基因的表达上调,调节了肠道免疫响应能力和健康水平,有利于哺乳期牦牛犊牛的健康高质量培育。

关键词： Cancer immunotherapy   Interleukin-12   Interleukin-17   Oncolytic virus   PD-L1  

摘要： Cancer immunotherapy has recently achieved a breakthrough status, however, it is not effective in all cancer types. Genetically engineered oncolytic viruses (OVs) with immunomodulators are promising new therapeutic modalities for cancer. CARG-2020 is an engineered trivalent oncolytic viral construct that specifically expresses three immune modulators that inhibit IL-17RA signaling and regulate PD-L1 expression by shRNAs, along with the cytokine IL-12 which activates multiple tumoricidal pathways. Previous work showed that intratumoral (i.t.) injection of CARG-2020 exhibits robust efficacy against established colorectal cancer (CRC). In this study, we report that systemic delivery of CARG-2020 via the intravenous (i.v.) route can successfully control CRC growth. To further expand the scope of CARG-2020 as a pan-cancer candidate, we also show that CARG-2020 works in two additional mouse models of melanoma and triple-negative breast cancer. Administration of CARG-2020 resulted in increased accumulation of CD8 T lymphocytes in the tumors, and depletion of these T cells results in poor tumor regression mediated by CARG-2020. Overall, our study shows a broad-spectrum efficacy of CARG-2020 in solid tumors and demonstrates the potential of CARG-2020 to be developed as a clinical candidate for the treatment of multiple human cancers that are surgically accessible.

关键词： apoptosis   angiogenesis   inflammation   ovarian ischemia/reperfusion   pirfenidone  

摘要： Objective Ovarian ischemia/reperfusion (I/R) injury is a common gynecological emergency, typically caused by ovarian torsion. Pirfenidone (PFN) has demonstrated potential therapeutic benefits due to its antioxidant, anti-inflammatory, and antiapoptotic properties. This research aimed to investigate the protective effects of PFN in alleviating ovarian I/R injury in female *** Female rats received PFN (300 mg/kg/day) for 3 consecutive days, either with or without the induction of ovarian I/R. The study assessed markers of ovarian oxidative stress, inflammation, apoptosis, and the levels of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor-A (VEGF-A). Ovarian histology was analyzed, along with immunohistochemical staining for Toll-like receptor 4 (TLR4) and p38 mitogen-activated protein kinase (p38 MAPK).Key findings I/R injury resulted in increased oxidative stress, inflammation, apoptosis, and a significant reduction in ovarian VEGF-A levels. Histological examination revealed ovarian damage, with increased expression of TLR4 and p38 MAPK. PFN treatment significantly improved the hormonal balance and mitigated oxidative stress, inflammatory, and apoptotic markers to normal levels. In addition, PFN improved ovarian tissue morphology and decreased TLR4 and p38 MAPK *** The findings suggest that PFN may offer protective effects against ovarian I/R injury through its antioxidant, anti-inflammatory, and antiapoptotic properties, as well as by promoting angiogenesis in the ovary.