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关键词： sHLA-E   sHLA-G   chronic lung allograft dysfunction   human cytomegalovirus   natural killer cell  

摘要： Plasma-soluble (s)HLA-G and sHLA-E are immunoregulatory proteins that balance the activation of NKG2A+ immune cells. In lung-transplant recipients (LTRs), dysregulated NKG2A+ natural killer cell responses may result in high-level human cytomegalovirus (HCMV) replication as well as chronic lung allograft dysfunction (CLAD), and especially the development of rapidly deteriorating CLAD is associated with high mortality. We thus analyzed the kinetics and function of sHLA-G and sHLA-E in follow-up samples of N = 76 LTRs to evaluate whether these immunoregulatory proteins are associated with the risk for CLAD and high-level HCMV replication. Here, we demonstrate that rapidly deteriorating CLAD LTRs are hallmarked by continually low (< 107 ng/ml) sHLA-G levels. In contrast, high sHLA-E levels were associated with the following development of high-level (> 1,000 copies/ml) HCMV episodes. Thus, sHLA-G and sHLA-E may serve as novel biomarkers for the development of rapidly deteriorating CLAD and high-level HCMV replication in LTRs. J Heart Lung Transplant 2024;43:2036-2041 (c) 2024 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://***/ licenses/by/4.0/).

关键词： HD   healthy donors   IFN   interferon   JAK   Janus kinase   MATE1   multidrug and toxin extrusion protein 1   NRP   nonresponder   OCT   organic cation transporter   OCTN1/2   organic cation transporter novel 1/2   PRP   partial responder   RP   responder   STAT1   signal transducer and activator of transcription 1   TNF   tumor necrosis factor   UC   ulcerative colitis   UC-IS   tofacitinib-insensitive UC   UC-IS1   tofacitinib-insensitive UC to both TNF-α+IFN-β and TNF-α+IFN-γ   UC-IS2   tofacitinib-sensitive UC in the presence of TNF-α+IFN-β, but not TNF-α+IFN-γ   UC-S   tofacitinib-sensitive UC  

关键词： T-cell therapy   TCR-pMHC interactions   Protein language models   TCR specificity   Peptide embeddings  

摘要： Cognate target identification for T-cell receptors (TCRs) is a significant barrier in T-cell therapy development, which may be overcome by accurately predicting TCR interaction with peptide-bound major histocompatibility complex (pMHC). In this study, we have employed peptide embeddings learned from a large protein language model- Evolutionary Scale Modeling (ESM), to predict TCR-pMHC binding. The TCR-ESM model presented outperforms existing predictors. The complementarity-determining region 3 (CDR3) of the hypervariable TCR is located at the center of the paratope and plays a crucial role in peptide recognition. TCR-ESM trained on paired TCR data with both CDR3 alpha and CDR3 beta chain information performs significantly better than those trained on data with only CDR3 beta, suggesting that both TCR chains contribute to specificity, the relative importance however depends on the specific peptide-MHC targeted. The study illuminates the importance of MHC information in TCR-peptide binding which remained inconclusive so far and was thought dependent on the dataset characteristics. TCR-ESM outperforms existing approaches on external datasets, suggesting generalizability. Overall, the potential of deep learning for predicting TCR-pMHC interactions and improving the understanding of factors driving TCR specificity are highlighted. The prediction model is available at http://***. in/ as an online tool.

关键词： HLA‐DRB1   NGS   bone marrow donor   novel allele  

摘要： Identification of four novel HLA-DRB1 alleles by next-generation sequencing.

关键词： acute lung injury   alveolar macrophages   cell death   monocyte-derived macrophages   TNF-alpha  

摘要： IntroductionAcute lung injury (ALI) and its subsequent progression to acute respiratory distress syndrome (ARDS) are severe respiratory conditions. They are marked by rapid lung function deterioration and extensive pulmonary inflammation, often resulting in critical patient outcomes. Alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs) are two distinct subsets of lung macrophages present in the alveoli during ALI. Both are critical mediators of pulmonary inflammation. Our study examined the interplay between AMs and MDMs in the inflammatory environment of ALI/*** were treated with lipopolysaccharide (LPS) to establish ALI models. The lung tissues of mice were subjected to hematoxylin-eosin staining to observe the degree of tissue damage. In vivo, CCR2-deficient mice or depleting peripheral blood mononuclear cells by clodronate liposomes were used to reduce MDMs recruitment. The bronchoalveolar lavage fluid (BALF) supernatants were used for cytokine and total protein analyses. AMs and MDMs in the BALF were analyzed by flow cytometry. The levels of AMs death were determined through propidium iodide staining and measured by flow cytometry. In vitro, primary AMs were exposed to MDM-conditioned medium or TNF-alpha, and their death levels were assessed under a fluorescence microscope with propidium iodide *** significantly decrease in number and undergo extensive cell death during ALI. The reduced MDMs recruitment can increase the number of AMs, reduce AMs death, and alleviate lung injury. In vitro, MDM-conditioned medium can induce AMs death and TNF-alpha is one of the major secretions. It indicates that TNF-alpha stimulation in vitro promotes AMs death. In vivo, MDMs are identified as the primary cells secreting TNF-alpha. Additionally, the treatment with TNF-alpha antagonists can reduce AMs death and the severity of lung *** study demonstrates that MDMs contribute to AMs death during ALI through TNF-alpha. Tar

关键词： Interleukin 6   MD simulation   Protein-protein interactions   Cytokine release syndrome   COVID-19  

摘要： Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19. Given the pivotal role of IL-6 cytokine in initiating CRS, it has been considered a most potential therapeutic target to mitigate hyperactivated immune responses. While monoclonal antibodies of IL-6 show promise in mitigating cytokine storm, concerns about immunotoxicity persist, and small molecule IL-6 antagonists remain unavailable. The present study employed sophisticated computational techniques to identify potential hit compounds as IL-6 inhibitors, with the aim of inhibiting IL-6/IL-6R protein-protein interactions. Through ligand-based pharmacophore mapping and shape similarity in combination with docking-based screening, we identified nine hit compounds with diverse chemical scaffolds as potential binders of IL-6. Further, the MD simulation of 300 ns of five virtual hits in a complex with IL-6 was employed to study the dynamic behavior. To provide a more precise prediction, binding free energy was also estimated. The identified compounds persistently interacted with the residues lining the binding site of the IL-6 protein. These compounds displayed low binding energy during MMPBSA calculations, substantiating their strong association with IL-6. This study suggests promising scaffolds as potential inhibitors of IL-6/IL-6R protein-protein interactions and provides direction for lead optimization.

关键词： Fibrosis   IL-17   Injury   Lung   Th17   gamma delta T cells  

摘要： The pathobiology of IL-17 in lung fibrogenesis is controversial. Here we examined the role of IL-17A/F in bleomycin (BLM) and adenoviral TGF-beta 1-induced lung fibrosis in mice. In both experimental models, WT and IL17af-/- mice showed increased collagen contents and remodeled lung architecture as assessed by histopathological examination, suggesting that IL-17A/F is dispensable for lung fibrogenesis. However, IL17af-/- mice responded to the BLM challenge with perturbed lung leukocyte subset recruitment. More specifically, bleomycin triggered angiocentric neutrophilic infiltrations of the lung accompanied by increased mortality of IL17af-/- but not WT mice. WT bone marrow transplantation failed to correct this phenotype in BLM-challenged IL17af-/- mice. Conversely, IL17a/f-/- bone marrow transplantation -> WT did not perturb lung leukocytic responses upon BLM. At the same time, IL17af-/- mice treated with recombinant IL-17A/F showed an attenuated lung inflammatory response to BLM. Together, the data show that the degree of BLM-driven acute lung injury was critically dependent on the presence of IL-17A/F, while in both models, the fibrotic remodeling process was not. Bleomycin-induced acute lung injury but not fibrosis is regulated in WT mice by the presence of radioresistant innate IL-17A/F-producing T cells and is exacerbated in IL17af-/- mice. Recombinant IL-17A/F therapy but not WT bone marrow transplantation ameliorates bleomycin induced acute lung injury in IL17af-/- mice. image

关键词： HLA   NGS   novel allele  

摘要： HLA-C*03:656 differs from HLA-C*03:04:01:02 by a single missense nucleotide substitution in codon 342 in exon 7.

关键词： CD169   COVID-19 waves   HLA-DR   PASC   Systemic immune-inflammation index  

摘要： The use of CD169 as a marker of viral infection has been widely discussed in the context of COVID-19, and in particular, its crucial role in the early detection of SARS-CoV-2 infection and its association with the severity and clinical outcome of COVID-19 were demonstrated. COVID-19 patients show relevant systemic alteration and immunological dysfunction that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). It is critical to implement the characterization of the disease, focusing also on the possible impact of the different COVID-19 waves and the consequent effects found after infection. On this basis, we evaluated by flow cytometry the expression of CD169 and HLA-DR on monocytes from COVID-19 patients and PASC individuals to better elucidate their involvement in immunological dysfunction, also evaluating the possible impact of different pandemic waves. The results confirm CD169 RMFI is a good marker of viral infection. Moreover, COVID-19 patients and PASC individuals showed high percentage of CD169+ monocytes, but low percentage of HLADR+ monocytes and the alteration of systemic inflammatory indices. We have also observed alterations of CD169 and HLA-DR expression and indices of inflammation upon different COVID-19 waves. The persistence of specific myeloid subpopulations suggests a role of CD169+ monocytes and HLA-DR in COVID-19 disease and chronic post-infection inflammation, opening new opportunities to evaluate the impact of specific pandemic waves on the immune response impairment and systemic alterations with the perspective to provide new tools to monitoring new variants and diseases associated to emerging respiratory viruses.