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关键词： Model for End-Stage Liver Disease   MELD   Interleukin-1b   Alcohol-Related Hepatitis  

摘要： BACKGROUND AND AIMS: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1(3 has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1(3, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function >= 32 but Model for End-Stage Liver Disease <= 27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS: CAN therapy in severe AH participants with Model for End-Stage Liver Disease <= 27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79;***, Number: NCT03775109.

关键词： HLA-B   NGS   novel allele   silent mutation  

摘要： Five novel HLA-B silent variants, HLA-B*08:01:81, HLA-B*18:01:59, HLA-B*35:01:82, HLA-B*35:03:45, and HLA-B*51:17:02, were detected by next-generation sequencing.

关键词： HLA-E   NKG2A/CD94   peptide/receptor interactions   T cell receptor  

摘要： The virtually monomorphic antigen presentation molecule HLA-E can present self- and non-self peptides to the NKG2A/CD94 co-receptor inhibitory complex expressed on natural killer (NK) cells and to T cell receptors (TCRs) expressed on T cells. HLA-E presents self-peptides to NKG2A/CD94 to regulate tissue homeostasis, whereas HLA-E restricted T cells mediate regulatory and cytotoxic responses toward pathogen-infected cells. In this study, we directly compared HLA-E/peptide recognition and signaling between NKG2A/CD94 and 2 HLA-E restricted TCRs that can recognize self-peptides or identical peptide mimics from the viral UL40 protein of cytomegalovirus using position substituted peptide variants. We show that position 7 is critical for interaction with NKG2A/CD94, whereas position 8 is important for interaction with the TCRs. The Arginine at position 5 of these peptides is an essential residue for recognition by both receptors. Thus, NKG2A/CD94 and TCRs have different requirements for recognition of peptides presented in HLA-E.

关键词： Porcine epidemic diarrhea virus   nsp14   RIG-I   IFN-beta   Innate immunity  

摘要： Porcine epidemic diarrhea virus (PEDV) is enteropathogenic coronavirus, and mainly damages intestines, causing diarrhea, vomiting, anorexia, and depression. PEDV highly pathogenic strains spread rapidly and pose significant economic and public health concerns in our country. After virus invasion, RIG-I detects viral double- stranded RNA to activate antiviral innate immunity, inducing IFN responses. PEDV genome encodes 16 non- structure proteins (nsp1-nsp16). These nsps have been effectively involved in the interaction of PEDV and host. PEDV nsp14 is a bi-functional enzyme that is responsible for proofreading and RNA cap G-N-7 methylation during viral infection. In this study, we confirmed that PEDV nsp14 was an interferon antagonist and inhibited IFN production induced by SeV and Poly(I:C). Further, we declared that PEDV infection decreased protein level of RIG-I, and the PEDV nsp14 played a part in this inhibitory effect. PEDV nsp14 induced cell apoptosis and then degraded RIG-I through caspase 8 and caspase 9 pathway during PEDV infection. The N7 MTase domain was critical for nsp14-mediated degradation of RIG-I. Our results revealed the novel function of PEDV nsp14 in virus- host interaction and provided a potential antiviral drug target.

关键词： asthma   biologics   biomarkers  

摘要： BackgroundIn patients with severe asthma, treatment with anti-interleukin-5 (IL-5) biologics can lead to a reduction in fractional exhaled nitric oxide (FeNO) in some patients. The clinical implications of varying FeNO responses to anti-IL-5 biologics remain unclear. This study aims to categorise patients based on their FeNO response to anti-IL-5 biologics and evaluate the association of these categories with clinical *** used the Danish Severe Asthma Register (DSAR) to identify the early FeNO response profiles in patients receiving anti-IL5 biologics. We defined FeNO responders as patients with elevated FeNO levels at baseline and a decrease corresponding to the minimal clinically important difference (MCID) at 4 months of follow-up and FeNO non-responders as those who did not experience a *** identified 403 patients on anti-IL5 treatment in DSAR, and 265 (66%) had elevated FeNO levels at baseline. After 4 months of treatment, 151 (57%) patients showed a significant decrease in FeNO levels, and 114 (43%) did not. FeNO responders were more likely to achieve clinical remission of asthma (34% vs. 19%, p = 0.01, OR 2.11, CI 1.04, 5.18, p = 0.03) than FeNO non-responders after 12 months of treatment. The higher remission rates in FeNO responders mainly reflected a higher rate of normalisation of lung *** levels were reduced after anti-IL5 treatment in a significant proportion of patients treated with anti-IL5, and this was associated with clinical remission. Early FeNO response to anti-IL5 could potentially be used as a biomarker to guide management decisions with biologics towards remission of disease in severe asthma.

关键词： MHC   multiepitope vaccine   neutralization   pan-variant   peptides   SARS-CoV-2   vaccine  

摘要： The development of a globally effective COVID-19 vaccine faces significant challenges, particularly in redirecting the B-cell response from immunodominant yet variable regions of viral proteins toward their conserved domains. To address this, an integrated strategy is implemented that combines classical B-cell epitope prediction with protein-antibody cluster docking and antibody titer analysis from 30 vaccinated and convalescent individuals. This approach yields stable immunodominant and immunoprevalent B-cell epitopes capable of eliciting robust antibody responses in BALB/c mice and effectively neutralizing pseudoviruses expressing the Spike protein of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, Delta, and Omicron. To achieve a broader T-cell-based immune response, promiscuous T-cell epitopes are identified by integrating classical T-cell epitope predictions, differential scanning fluorimetry, and peptide-MHC structural analysis. Unique peptides with conserved MHC-anchoring residues are identified, enabling binding to a spectrum of MHC-I and MHC-II haplotypes. These peptides elicit strong interferon gamma responses in human peripheral blood mononuclear cells and demonstrate cross-species efficacy by activating both CD4+ and CD8+ T-cells in BALB/c mice. Collectively, these findings highlight the significance of innovative vaccine strategies targeting immunodominant/immunoprevalent B-cell and promiscuous T-cell epitopes to drive broad and robust humoral and cellular immune responses against a wide range of SARS-CoV-2 variants.

关键词： HLA class I   HLA-B   HLA-C   novel alleles  

摘要： Sequencing of the novel alleles HLA-B*15:727 and HLA-C*04:01:01:194Q.

关键词： bispecific antibodies   bystander killing   cancer immunotherapy   T-cells  

摘要： Bispecific antibodies (bsAbs) bridging CD3 on T-cells to tumor-associated antigens (TAA) on tumor cells can direct T-cell immunity to solid tumors. "Bystander killing", where T-cell targeting of TAA-positive tumor cells also leads to the eradication of TAA-negative cells, may overcome TAA heterogeneity. While bystander activity of activated, engineered T-cells has been shown to be robust and wide-reaching, spatiotemporal aspects of bsAb-mediated bystander activity are unresolved. Here, we developed a model where breast cancer tumoroids varying in HER2 expression were printed in to extracellular matrix (ECM) scaffolds. We generated (1) mixed tumors containing different ratios of HER2+ and HER2- tumor cells, and (2) HER2+ and HER2- tumoroids spaced at different distances within the ECM scaffold. Subsequently, tumors were exposed to peripheral blood-derived T-cells in the presence of CD3xHER2 bsAbs. We find that CD3xHER2 bsAb-mediated interaction of resting, nonactivated T-cells with HER2+ tumor cells is sufficient (1) to eliminate 50% HER2- cells in mixed tumor areas, and (2) to eradicate distant HER2- tumor areas. Such bystander killing involves paracrine IFN gamma and TNF alpha activity but does not require T-cell accumulation in HER2- areas. These findings indicate that bystander eradication of TAA-negative cells can significantly contribute to bsAb therapy for solid tumors.