Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.
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ABSTRACT:
SUBMITTER: Declercq J
PROVIDER: S-EPMC8555973 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7267751 | biostudies-literature
Project description:Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). As PGs play diverse biological roles in homeostasis and inflammatory responses, inhibiting PG production with NSAIDs could affect COVID-19 pathogenesis in multiple ways, including: (1) altering susceptibility to infection by modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; (2) regulating replication of SARS-CoV-2 in host cells; and (3) modulating the immune response to SARS-CoV-2. Here, we investigate these potential roles. We demonstrate that SARS-CoV-2 infection upregulates COX-2 in diverse human cell culture and mouse systems. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication. In contrast, in a mouse model of SARS-CoV-2 infection, NSAID treatment reduced production of pro-inflammatory cytokines and impaired the humoral immune response to SARS-CoV-2 as demonstrated by reduced neutralizing antibody titers. Our findings indicate that NSAID treatment may influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies rather than modifying susceptibility to infection or viral replication.ImportancePublic health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19). NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are critical for the generation of prostaglandins - lipid molecules with diverse roles in homeostasis and inflammation. Inhibition of prostaglandin production by NSAIDs could therefore have multiple effects on COVID-19 pathogenesis. Here, we demonstrate that NSAID treatment reduced both the antibody and pro-inflammatory cytokine response to SARS-CoV-2 infection. The ability of NSAIDs to modulate the immune response to SARS-CoV-2 infection has important implications for COVID-19 pathogenesis in patients. Whether this occurs in humans and whether it is beneficial or detrimental to the host remains an important area of future investigation. This also raises the possibility that NSAIDs may alter the immune response to SARS-CoV-2 vaccination.
| S-EPMC8092681 | biostudies-literature
Project description:The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID-19, and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T-cell engagers and chimeric antigen receptor (CAR) T cells. CRS is intimately linked with dysregulated and excessive cytokine release, including IFN-γ, TNF-α, IL 1, IL-6, and IL-10, resulting in a systemic inflammatory response leading to multiple organ failure. Here, we show that mice intravenously administered the agonistic hamster anti-mouse CD3ε monoclonal antibody 145-2C11 develop clinical and laboratory manifestations seen in patients afflicted with CRS, including body weight loss, hepatosplenomegaly, thrombocytopenia, increased vascular permeability, lung inflammation, and hypercytokinemia. Blood cytokine levels and gene expression analysis from lung, liver, and spleen demonstrated a hierarchy of inflammatory cytokine production and infiltrating immune cells with differentiating organ-dependent kinetics. IL-2, IFN-γ, TNF-α, and IL-6 up-regulation preceded clinical signs of CRS. The co-treatment of mice with a neutralizing anti-cytokine antibody cocktail transiently improved early clinical and laboratory features of CRS. We discuss the predictive use of this model in the context of new anti-cytokine strategies to treat human CRS.
| S-EPMC8237068 | biostudies-literature
Project description:We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-? to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1?, CCL5, and CXCL10 production, and antiviral interferon-? and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-?B pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3+ eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4+CRTH2+ Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
| S-EPMC7264207 | biostudies-literature
Project description:Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-? using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-?B activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-? and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.
| S-EPMC7443334 | biostudies-literature
Project description:A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1β, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.
| S-EPMC10953344 | biostudies-literature
Project description:The year 2020 witnessed a heavy death toll due to COVID-19, calling for a global emergency. The continuous ongoing research and clinical trials paved the way for vaccines. But, the vaccine efficacy in the long run is still questionable due to the mutating coronavirus, which makes drug re-positioning a reasonable alternative. COVID-19 has hence fast-paced drug re-positioning for the treatment of COVID-19 and its symptoms. This work builds computational models using matrix completion techniques to predict drug-virus association for drug re-positioning. The aim is to assist clinicians with a tool for selecting prospective antiviral treatments. Since the virus is known to mutate fast, the tool is likely to help clinicians in selecting the right set of antivirals for the mutated isolate. The main contribution of this work is a manually curated database publicly shared, comprising of existing associations between viruses and their corresponding antivirals. The database gathers similarity information using the chemical structure of drugs and the genomic structure of viruses. Along with this database, we make available a set of state-of-the-art computational drug re-positioning tools based on matrix completion. The tools are first analysed on a standard set of experimental protocols for drug target interactions. The best performing ones are applied for the task of re-positioning antivirals for COVID-19. These tools select six drugs out of which four are currently under various stages of trial, namely Remdesivir (as a cure), Ribavarin (in combination with others for cure), Umifenovir (as a prophylactic and cure) and Sofosbuvir (as a cure). Another unanimous prediction is Tenofovir alafenamide, which is a novel Tenofovir prodrug developed in order to improve renal safety when compared to its original counterpart (older version) Tenofovir disoproxil. Both are under trail, the former as a cure and the latter as a prophylactic. These results establish that the computational methods are in sync with the state-of-practice. We also demonstrate how the drugs to be used against the virus would vary as SARS-Cov-2 mutates over time by predicting the drugs for the mutated strains, suggesting the importance of such a tool in drug prediction. We believe this work would open up possibilities for applying machine learning models to clinical research for drug-virus association prediction and other similar biological problems.
| S-EPMC8079380 | biostudies-literature
Project description:Coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome-coronavirus-2 is a worldwide public health emergency that will have a lasting generational impact in terms of mortality and economic devastation. Social distancing to prevent viral transmission and supportive care of infected patients are the main interventions now available. This global health crisis therefore merits innovative therapies. Cytokine release syndrome mediated by interleukin-6 is a critical driver of coronavirus disease 2019 mortality. Herein, we review and discuss key immunologic effects of direct interleukin-6 blockade, downstream nonselective Janus kinase inhibition, and selective Janus kinase 2 suppression to treat coronavirus disease 2019-related cytokine release syndrome. We provide evidence that selective targeting of interleukin-6 or Janus kinase 2 is well informed by existing data. This contrasts with broad, nonselective blockade of Janus kinase-mediated signaling, which would inhibit both deleterious and beneficial cytokines, as well as critical host antiviral immunity.
| S-EPMC7314334 | biostudies-literature
Project description:Since the beginning of the SARS-CoV-2 pandemic, the treatments and management of the deadly COVID-19 disease have made great progress. The strategies for developing novel treatments against COVID-19 include antiviral small molecule drugs, cell and gene therapies, immunomodulators, neutralizing antibodies, and combination therapies. Among them, immunomodulators are the most studied treatments. The small molecule antiviral drugs and immunoregulators are expected to be effective against viral variants of SARS-CoV-2 as these drugs target either conservative parts of the virus or common pathways of inflammation. Although the immunoregulators have shown benefits in reducing mortality of cytokine release syndrome (CRS) triggered by SARS-CoV-2 infections, extensive investigations on this class of treatment to launch novel therapies that substantially improve efficacy and reduce side effects are still warranted. Moreover, great challenges have emerged as the SARS-CoV-2 virus quickly, frequently, and continuously evolved. This review provides an update and summarizes the recent advances in the treatment of COVID-19 and in particular emphasized the strategies in managing CRS triggered by SARS-CoV-2. A brief perspective in the battle against the deadly disease was also provided.
| S-EPMC9124488 | biostudies-literature
Project description:CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.
| S-EPMC4623119 | biostudies-literature