Search

Despite the growing use of desensitization strategies, hyperimmune patients remain at high risk of antibody-mediated rejection suggesting that, even when donor-specific antibodies (DSA) are effectively depleted, anti-donor specific B cells persist. We included 10 highly sensitized recipients that underwent desensitization with plasmapheresis and B cell depletion prior to kidney transplantation. We quantified changes in DSA (luminex), total B-cell subsets (flow cytometry), anti-donor HLA B cells (fluorospot), and single-cell metabolism in serially collected samples before desensitization, at the time of transplant, and at 6 and 12 months thereafter. Desensitization was associated with a decrease in DSA and total memory B cell and naive B cell percentage, while plasma cells and memory anti-donor HLA circulating B cells persisted up to 12 months after transplant. At 12-month post-transplantation, memory B cells increased their glycolytic capacity, while proliferative KI67+ plasma cells modified their metabolism by increasing fatty acid and amino acid oxidation capacity and decreasing their glucose dependence. Despite effective DSA depletion, anti-donor B cells persist in kidney transplant recipients. Due to the reliance of these cells on glycolysis, glycolysistargeting therapies might represent a valuable treatment strategy. [ABSTRACT FROM AUTHOR]

Résumé: L'immunologie hépatique est très spécifique et l'immunotolérance hépatique est particulièrement développée en raison de l'afflux constant et massif d'antigènes liés à la proximité du foie avec le tube digestif. La dérégulation de l'immunotolérance hépatique est impliquée dans le développement des maladies hépatiques chroniques et peut favoriser la cancérogenèse hépatique avec une physiopathologie particulièrement complexe. Cette immunotolérance exacerbée suggère que le carcinome hépatocellulaire (CHC) est un bon candidat aux immunothérapies telles que les inhibiteurs de checkpoints immuns, qui visent à restaurer l'immunité anti-tumorale, défaillante dans cette situation. Néanmoins, les taux de réponse tumorale objective chez les patients atteints de CHC traités avec des inhibiteurs de PD-L1/PD-1 sont d'environ 15-20 % seulement, suggérant que ces thérapies ne fonctionnent que sous certaines conditions. Par ailleurs, des réponses durables peuvent être observées chez ces répondeurs, suggérant que leur identification, grâce au développement de marqueurs prédictifs de réponse efficaces, est un des enjeux majeurs pour améliorer la prise en charge du CHC. Dans cette mini-revue, nous décrivons les principales voies impliquées dans l'immunotolérance hépatique physiologique et lors de la carcinogénèse hépatique, et nous abordons les différents marqueurs pronostiques et prédictifs de réponse qui pourraient aider à sélectionner de manière optimale les patients atteints de CHC dans le futur. Liver immunology is very specific and immunotolerance is particularly developed due to the constant and massive influx of antigens induced by the proximity of the liver with the digestive tract. Deregulation of liver immunotolerance is involved in the development of chronic liver diseases and can promote hepatic carcinogenesis with complex pathophysiological mechanisms. This aberrant immunotolerance suggests that hepatocellular carcinoma (HCC) is a good candidate for immunotherapies such as immune checkpoint inhibitors, which aim to restore anti-tumor immunity, failing in this situation. However, the objective tumor response rates in HCC patients treated with PD-L1/PD-1 inhibitors are only around 15-20%, suggesting that these therapies work only under certain conditions. In addition, sustained responses can be observed in these responders, suggesting that their identification, thanks to the development of effective predictive response markers, is one of the key challenges for improving the management of HCC. In this short review, we describe the main pathways involved in liver immunotolerance and in HCC immune escape, and we discuss the different prognostic and predictive response markers that could help to optimally select patients with HCC in the future. [ABSTRACT FROM AUTHOR]

Background & Aims The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterized in patients with liver fibrosis. Methods In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization and localization of IL-17+ cells. Results Density of IL-17+ cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; P < 0.0001). Data clearly show that the frequency of intrahepatic IL-17+ lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis, and we observed no statistical differences in number of IL-17+ macrophages during progression of fibrosis. On the other hand, the number of IL-17+ neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; P < 0.0001), contributing significantly to total IL-17 production in liver tissue. Conclusions Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry has a pervasive need for chiral specific molecules with optimal affinity for their biological targets. However, the mass production of such compounds is currently limited by conventional chemical routes, that are costly and have an environmental impact. Here, we propose an easy access to obtain new tetrahydroquinolines, a motif found in many bioactive compounds, that is rapid and cost effective. Starting from simple raw materials, the procedure uses a proline-catalyzed Mannich reaction followed by the addition of BF 3  ⋅ OEt 2 , which generates a highly electrophilic aza-ortho-quinone methide intermediate capable of reacting with different nucleophiles to form the diversely functionalized tetrahydroquinoline. Moreover, this enantioselective one-pot process provides access for the first time to tetrahydroquinolines with a cis-2,3 and trans-3,4 configuration. As proof of concept, we demonstrate that a three-step reaction sequence, from simple and inexpensive starting compounds and catalysts, can generate a BD2-selective BET bromodomain inhibitor with anti-inflammatory effect., (© 2022 Wiley-VCH GmbH.)