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Introduction: Granulocytes are innate immune cells that play a key role in pathogen elimination. Recent studies revealed the diversity of granulocytes in terms of phenotype and function. In particular, a subset of granulocytes identified as low-density granulocytes (LDG) has been described in physiological conditions and with increased frequencies in several pathological contexts. However, the properties of LDG are still controversial as they vary according to the pathophysiological environment. Here we investigated the heterogeneity of granulocyte populations and the potential differences in phenotype and immunomodulatory capacity between LDG and normal density granulocytes (NDG) in people living with HIV-1 (PLWH)., Methods: To this end, we developed an optimized method to purify LDG and NDG from a single blood sample, and performed in-depth, comparative phenotypic characterization of both granulocyte subtypes. We also assessed the impact of purification steps on the expression of cell surface markers on LDG by immunophenotyping them at different stages of isolation., Results: We identified 9 cell surface markers (CD16, CD32, CD89, CD62L, CD177, CD31, CD10, CXCR4 and CD172α) differentially expressed between LDG and NDG. Noteworthy, markers that distinguish the two subsets include receptors for the Fc part of IgG (CD16, CD32) and IgA (CD89). Importantly, we also highlighted that the purification procedure affects the expression of several cell surface markers (i.e.CD63, CD66b, …) which must be taken into account when characterizing LDG. Our work sheds new light on the properties of LDG in PLWH and provides an extensive characterization of this granulocyte subset in which Fc receptors are key discriminatory markers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marsile-Medun, Souchard, Abba Moussa, Reynaud, Tuaillon, Naranjo-Gomez and Pelegrin.)

The multiple mechanisms of action of antiviral monoclonal antibodies (mAbs) have made these molecules a potential therapeutic alternative for treating severe viral infections. In addition to their direct effect on viral propagation, several studies have shown that mAbs are able to enhance the host's adaptive immune response and generate long-lasting protective immunity. Such immunomodulatory effects occur in an Fc-dependent manner and rely on Fc-FcγR interactions. It is noteworthy that several FcγR-expressing cells have been shown to play a key role in enhancing humoral and cellular immune responses (so-called "vaccinal effects") in different experimental settings. This review recalls recent findings concerning the vaccinal effects induced by antiviral mAbs, both in several preclinical animal models and in patients treated with mAbs. It summarizes the main cellular and molecular mechanisms involved in these immunomodulatory properties of antiviral mAbs identified in different pathological contexts. It also describes potential therapeutic interventions to enhance host immune responses that could guide the design of improved mAb-based immunotherapies.

Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations. Trial registration: ClinicalTrials.gov identifier: NCT04093596.

Biliary secretion was studied in normolipidemic rats after a 7 day treatment with the hypolipidemic drugs, tiadenol (bis-(hydroxyethylthio)-1,10-decane), clofibrate and clofibride (chloro-4-phenoxy-2-methyl-2-propionate of dimethylcarbamoyl-3-propyl). All three drugs decreased blood cholesterol and total lipids, increased liver weight and liver catalase content, and decreased biliary excretion of cholesterol. The biliary concentrations of bile salts, phospholipids and cholesterol decreased to a variable extent, in such a way that the ratio of bile salts + phospholipids to cholesterol was increased by the drugs. The bile salt independent fraction was increased. The effects were qualitatively similar for all three drugs tested, but quanitative differences appeared for some of the parameters.

The regenerating rat liver after partial hepatectomy was used as a model to study the effects of an hypolipidaemic drugs, tiadenol (bis hydroxyethylthio 1--10 decane). Seven days after partial hepatectomy, liver weight, DNA, RNA, total protein and cytochrome P-450 were increased in tiadenol treated rats, relative to hepatectomized controls. Tiadenol displaying similar effects on the intact liver, it is concluded that this hypolipidaemic drug maintains its hepatomegalic action on the regenerating rat liver.

1. Acute galactosamine (Gal) hepatitis was induced in rats drinking ad libitum either sodic bicarbonated water of Vichy Grande Grille (GG) or ordinary tap water (OH2). Two series of experiments were performed. 2. In the first series, Gal-induced hepatitis was moderate. Twenty four hours after IP Gal injection, GG treated rats had relative to OH2 treated rats a decrease of bile flow and BSP excretion, and an increase of serum transaminase and bilirubin. Seven days after Gal the liver had returned to normal except for an increase in biliary bilirubin and liver total lipids. 3. In the second series, Gal-induced hepatitis was severe. Twenty four hours after galactosamine administration, an increase in mortality after anesthesia was found in Gal/GG rats. An increase of liver size and total hepatic lipids was also observed, while bile secretion, BSP excretion, cyt P 450 and ARN decreased in Gal/GG rats. Steatosis and inflammatory reactions were more important in Gal/GG than in Gal/OH2 rats. Most parameters came back to their normal levels in two days in Gal/OH2 rats, while 7 days were generally necessary in Gal/GG treated animals. Hepatic DNA kept increasing in Gal/GG animals and was still higher after 7 days, maybe due to a greater inflammatory reaction in the liver, maybe following a stimulated hepatocyte regenerative response. 4. These results indicate that GG water is not an inoffensive salt solution.

Pancreatic secretion and pancreatic enzyme contents were studied in rats given orally methadone for six months (10 to 50 mg . kg-1 . day-1 in drinking water). The main results were as follows: 1. In conditions of acute pancreatic fistula under urethane anesthesia: (a) basal concentration of total protein increased in the juice (+23 p. 100, p less than 0,05). The increase in trypsinogen appeared larger than that of other enzymes; (b) under conditions of maximal stimulation by 2 deoxy-glucose (2 DG), all secretory parameters were increased (protein x 2.7, p less than 0.05; sodium x 1.7, p less than 0.02; bicarbonate x 1.8, p less than 0.05); (c) under conditions of maximal electrical stimulation of the vagus, pancreatic response was unsignificantly increased; (d) dose-response curves to secretin and CCK-PZ were unsignificantly changed. 2. Pancreatic weight was not changed. In the pancreatic tissue: (a) total protein decreased (-10 p. 100, p less than 0.01) as well as amylase (-30 p. 100 p less than 0.001), lipase (-19 p. 100, p less than 0.01) and trypsinogen (-9 p. 100, NS); (b) concentrations of DNA and RNA were unsignificantly increased; (c) histological structure was normal in optical microscopy. 3. Antral gastrin cell numbers were not changed. 4. In conclusion, a decrease in pancreatic enzymatic contents, associated with an increase of total protein in basal secretion and after maximal stimulation by 2DG are consistent with the hypothesis of an increase in synthesis and a decrease in turnover time of exportable proteins in the pancreatic tissue of methadone treated rats. No chronic pancreatitis was observed in these conditions. Endogenous gastrin was probably not involved in pancreatic changes observed.

Two types of pancreatic fistulas were directly compared in Wistar rats, to define more accurately the differences between collecting pancreatic juice under anesthesia (acute fistula) and in awake restrained animals (chronic fistula). Basal outputs of water, bicarbonate and total protein were about then times larger in chronic than in acute animals; they could be larger than the maximal secretory rate in anaesthetized rats. As a corollary, the chronic preparation was less sensitive to ecbolic and hydrelatic stimulations, with respect to basal levels. It is concluded that chronic fistula rats display a highly stimulated state of pancreatic secretion, probably due to the potentiation of several neurohumoral factors. Whatever this stimulation originates from, it renders the model less suitable for studies on ancreatic stimulating agents. On the contrary, anaesthetized rats displayed a low secretion more responsive to stimulating agents.

The stimulatory effects of isoproterenol and secretin on external pancreatic secretion were compared in the rat. 1. In acute fistula, pylorus ligation, atropine, glucagon did not change either of the stimulated secretions. Propranolol inhibited isoproterenol-induced secretion and did not change secretin induced stimulation. Theophylline alone displayed a large hydrelatic stimulatory effect, without increasing protein excretion; the effect of theophylline was additive with the effects of isoproterenol or secretin but no evidence was found of potentiation or prolongation of action. Isoproterenol did not increase pancreatic blood flow and induced no variations in the plasma levels of immunoreactive secretin. Combining various doses of isoproterenol and secretin did not allow to reach secretory levels greater than the maximal response to secretin. 2. In conscious rats chronic fistulae, isoproterenol and secretin had a distinct effect.