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关键词： CD8+ T cells   COVID-19   HLA-B*15:01   T cell receptors   severe disease  

摘要： Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8 T-cells directed against HLA-B*15:01-restricted Spike-derived S peptide (B15/SCD8 T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8 T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/SCD8 T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/SCD8 T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/SCD8 T-cell responses lacking a highly expanded key public B15/SCD8 T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/SCD8 T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/SCD8 T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/SCD8 T-cells did not differ across disease severity. Moreover, B15/SCD8 T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

摘要： Abstract During double umbilical cord blood transplant (DUCBT), the winning unit (WU) rejects the losing unit (LU) because of WU T cells directed against the LU mismatched HLA. This immune response might protect against relapse, especially when the patient and LU (PT-LU) share the same mismatch with the WU. To validate this hypothesis, a retrospective Eurocord study, conducted on 383 DUCBTs, focused on posttransplant relapse and HLA mismatches between PT-LU and the WU. A PT-LU HLA-A mismatch shared with the WU was associated with a lower 7-year relapse incidence (16% vs 28%; P = .048). In addition, multiple PT-LU shared HLA mismatches were also associated with a lower relapse risk (7% vs 29%; P = .003). In DUCBT with ≥2 HLA mismatches between patient and WU, the number of HLA mismatches between those did not significantly affect relapse incidence, whereas multiple PT-LU shared HLA mismatches remained associated with a lower relapse risk (7% vs 29%; P = .0038). Finally, considering patients who did not develop either grade 2 to 4 acute graft-versus-host disease or chronic graft-versus-host disease, a PT-LU shared HLA-A mismatch as well as multiple PT-LU HLA mismatches shared with the WU remained associated with a significantly lower 7-year relapse incidence. In multivariate adjusted analyses multiple PT-LU shared HLA mismatches remained associated with a significantly reduced 7-year posttransplant relapse risk. Our analysis indicates that, during DUCBT, PT-LU shared HLA mismatches prime an immune response of the WU against leukemia, reducing the long-term risk of posttransplant relapse, and that DCBT has particular utility in those with high-risk leukemia.

摘要： BackgroundGX-I7 (rhIL-7-hyFc, efineptakin alfa) is a hybrid Fc-fused long-acting interleukin-7 (IL-7) with the aim of correcting T-cell deficiency, thereby strengthening the immune response to fight against cancer. This Phase 1b, dose-escalation study was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GX-I7 in patients with locally advanced or metastatic solid *** study, conducted in patients with advanced solid tumours at three hospitals in Korea, involved intramuscular GX-I7 administration across eight dose levels (60-1700 mu g/kg) in 3- and 6-week cohorts. A dose-expansion phase at 720 and 1200 mu g/kg further assessed GX-I7's safety and ***-tumour responses showed either stable disease (SD) or disease progression (PD). GX-I7 demonstrated dose-dependent increases in the maximum serum concentration (Cmax) and area under the curve up to the last measurable concentration (AUClast). In addition, a dose-dependent increase in circulating CD8+/CD4+ T cells was observed. In five patients who consented for biopsy, a statistically significant increase in tumour-infiltrating lymphocytes (TILs) followed GX-I7 *** suggest GX-I7 is a safe T cell-amplifying agent with peripheral immune activation. Ongoing studies are exploring its ability to enhance immune responses in peripheral immune cells and tumour cells when combined with other anti-cancer *** Trial registrationNCT03478995

摘要： This review examines the expanding role of non-human leukocyte antigen (non-HLA) genetic factors in kidney transplantation, with a particular focus on their implications for living donor evaluation and outcomes. It emphasizes the potential of genetic testing to improve risk stratification beyond conventional HLA matching, especially for donor candidates with a family history of hereditary kidney disease. Non-HLA genetic mismatches, including single nucleotide variants affecting minor histocompatibility antigens, can drive alloimmune responses, leading to graft rejection and failure even in HLA-matched transplants. The presence of non-HLA antibodies further contributes to adverse immunological outcomes. Genetic testing in related living donors can uncover monogenic kidney diseases, enabling early identification of at-risk individuals and enhancing donor safety. While polygenic risk scores and gene panels show promise in predicting complications and guiding post-transplant care, most genome-wide association studies have focused on recipients. There remains a significant gap in understanding how donor-specific genetic factors influence post-donation kidney function and long-term health outcomes. The integration of non-HLA genetic testing into living donor evaluation supports a precision medicine approach to kidney transplantation, offering improved risk assessment and donor-recipient matching. As the field advances, longitudinal studies and robust data collection, particularly around donor genetics, are essential to optimize transplant outcomes, inform clinical decision-making, and uphold ethical standards in donor care.

关键词： L-glutamine   Lipopolysaccharide   Retinal inflammation   IGF-2   NF-kappa B/NLRP3/IL-18 axis  

摘要： Regarding retinal inflammation, NF-kappa B activation has been demonstrated to stimulate the NLRP3 inflammasome, which subsequently promotes IL-18 production, resulting in heightened inflammatory damage. Concurrently, GLP-1 has shown a role in reducing the likelihood of retinal inflammation. Nonetheless, the exact mechanism by which GLP-1 can reduce inflammation in the retina by modulating NF-kappa B/NLRP3/IL-18 axis remains unknown. Therefore, it may be worthwhile investigating the effects of L-glutamine (L-glu), a GLP-1 inducer, on LPS-induced retinal inflammation in rats, considering the involvement of NF-kappa B/NLRP3/IL-18 signaling. This study utilized the strategy of network pharmacology with subsequent experimental validation to predict the targets and associated pathways related to L-glu and retinal inflammation. To authenticate the in vivo pharmacological efficacy of L-glu, 60 mice were divided into 4 groups. The expression and level of GLP-1, in addition to IGF-2 and IL-18 levels were assayed. Gene expression of PPAR gamma and XO, as well as protein expression of p-TLR4, SIRT1, NLRP3, and caspase-1 were determined. The Nrf2/HO-1, MDA, and TAC were also detected. Retinal histopathology and immunostaining were lastly done. Network analysis identified 251 overlapping targets and 462 pathways between L-glu and retinal inflammation. Experimentally, L-glu enhanced the IGF-2-dependent PPAR gamma expression by boosting GLP-1 secretion. PPAR gamma then restricted TLR4 phosphorylation and XO expression to activate SIRT1/Nrf2 and alleviate oxidative stress. SIRT1 simultaneously inhibited the NF-kappa B-driven secretion of TNF-alpha and IL-6, as well as the ensuing activation of NLRP3/caspase-1/IL-18. These findings suggested that L-glu may confer protection against LPS-induced retinal inflammation in a GLP-1-dependent manner via prohibiting NF-kappa B/NLRP3/IL-18 pathway.

关键词： Interleukin-16   Staphylococcus aureus   Pain   Hyperalgesia   Allodynia   Protein A  

摘要： Staphylococcus aureus is a Gram-positive bacteria that induces painful infections. Since S. aureus releases a protein called staphylococcal protein A (SpA) that can stimulate the release of interleukin IL-16 and the involvement of this interleukin in inflammatory pain has been recently demonstrated in mice, we explored whether SpA and IL-16 participate in S. aureus-evoked hypernociception. The intraplantar (***.) administration of SpA (0.3-3 mu g) produced thermal hyperalgesia and mechanical allodynia prevented by an anti-IL-16 antibody (0.3-1 mu g/kg). Moreover, the ***. inoculation of S. aureus (103-106 CFU, 6 h before) induced hyperalgesia and allodynia together with an increase of local concentrations of IL-16 and the up-regulation of caspase-3 mRNA. Immunofluorescence assays indicated that neutrophils are the main cells expressing IL-16 after S. aureus ***. injection. Supporting the involvement of IL-16, antibodies against IL-16 (1-30 mu g/kg) or CD4 receptors (1-30 mu g/kg) inhibited hyperalgesia and allodynia evoked by this microorganism. In contrast, the anti-IL-16 antibody did not alter hypernociception produced by Streptococcus pyogenes, another Gram-positive bacteria unrelated to SpA. Since septic arthritis is one of the main clinical entities related to S. aureus-induced pain, we inoculated S. aureus (2 x 105 CFU, 5 days before) into the knee. Hyperalgesia, allodynia and local IL-16 up-regulation were observed, being the presence of IL-16 mainly related to macrophage-like synovial cells and fibroblasts. Accordingly, the anti-IL-16 antibody also completely prevented hypernociceptive reactions in these mice. Overall, the present results support the possible relevance of IL-16 as an innovative target for the control of pain during S. aureus infections.

关键词： 急性淋巴细胞白血病   双特异性T细胞衔接器   贝林妥欧单抗   儿童  

摘要： 贝林妥欧单抗是一种同时靶向CD3和CD19的双特异性T细胞衔接器，通过激活内源性T淋巴细胞免疫识别功能并诱发大量炎症因子分泌可导致肿瘤细胞凋亡。美国食品药品监督管理局及中国国家药品监督管理局已批准用于治疗成人和儿童复发或难治性(R/R)前体B细胞急性淋巴细胞白血病(ALL)。随着临床研究的深入，贝林妥欧单抗应用指征不断前移。现就贝林妥欧单抗在儿童R/R ALL的治疗机制及临床研究进展进行综述。

关键词： Ionic Liquid mediated green synthesis   Microwave Irradiation   Van Leusen cycloaddition   Molecular Docking   Biological evaluation   DFT studies  

摘要： A novel, efficient, and facile protocol for the green synthesis of a series of various 3,4-disubstituted pyrroles via the Van-Leusen [3+2] cycloaddition of tosyl methyl isocyanide (TosMIC) and chalcones has been demonstrated under microwave irradiation conditions using an ionic liquid system viz. [PAIM][Cl]/[BMIM][X] as an environmentally benign reaction medium. The distinctive characteristics of this work include attractive features such as IL-mediated C-C bond formation, short reaction time, energy-efficient microwave irradiation, recycling, and reuse of ionic liquids, wide substrate scope, etc. Further, the in vitro antimicrobial potential of these analogues was examined against four bacterial and six fungal strains using the broth microdilution method. Among the 26 compounds, analogues bearing peripheral chloro, fluoro, methoxy, and nitro substitutions indicated good to excellent antimicrobial activities with a minimum inhibition concentration (MIC) up to 2 mu g/mL, combating microbial infections. To understand the structure-activity relationship (SAR), molecular docking and density functional theory (DFT) studies were also carried out, and the results were in good agreement with the antimicrobial activity profiles.

摘要： The aim of the work was to study changes in the content of ceramide and key enzymes involved in its biosynthesis, as well as TNFα content and TNFR1 expression levels, in the rat brain under conditions of acute cerebral ischemia (ACI) and hypoxic preconditioning (HP); additionally, we aimed to assess the relationship between these factors and animal survival rates and neurological deficit. The experiments were carried out on 37 male outbred white rats weighing 180–230 g. ACI was induced by irreversible ligation of the left common carotid artery combined with reversible ligation of the right common carotid artery. The animals were divided into three groups: group 1—sham-operated rats (control); group 2—rats exposed to ACI; and group 3—rats exposed to ACI and HP. On day 3 of observation, neurological deficit was assessed using the Garcia scale; changes in the levels of TNFα, TNFR1 expression, ceramide, serine palmitoyltransferase, ceramide synthase, and acid and neutral sphingomyelinases were evaluated by immunofluorescence microscopy. ACI led to increased ceramide production and elevated levels of all the ceramide-synthesizing enzymes in the brain, being also accompanied by higher levels of TNFα and upregulated TNFR1 expression. HP abated these effects, preventing the rise in ceramide, sphingomyelinase, and TNFα levels, as well as in TNFR1 expression, thereby reducing the severity of neurological deficits and improving animal survival rates compared to ACI. Thus, HP demonstrated its efficacy as a method to reduce neurological impairments and increase survival in experimental animals, as well as to partly prevent changes in pro-inflammatory factors and ceramide levels due to suppression of key enzymes involved in its synthesis.