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Michael B A Oldstone - One of the best experts on this subject based on the ideXlab platform.
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animal model of respiratory syncytial virus cd8 t cells cause a Cytokine Storm that is chemically tractable by sphingosine 1 phosphate 1 receptor agonist therapy
Journal of Virology, 2014Co-Authors: Kevin B Walsh, John R Teijaro, Hugh Rosen, Linda G Brock, Daniel M Fremgen, Peter L Collins, Michael B A OldstoneAbstract:The Cytokine Storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by Cytokine and immune cell components. The Cytokine Storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a Cytokine Storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8+ T cells infiltrated into the lung, initiating a Cytokine Storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited Cytokine Storm by blunting the PVM-specific CD8+ T cell response, resulting in diminished pulmonary disease and enhanced survival. IMPORTANCE A dysregulated overly exuberant immune response, termed a “Cytokine Storm,” accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the Cytokine Storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the Cytokine Storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these Cytokines with neutralizing antibodies blunts the Cytokine Storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
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mapping the innate signaling cascade essential for Cytokine Storm during influenza virus infection
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: John R Teijaro, Kevin B Walsh, Stephanie Rice, Hugh Rosen, Michael B A OldstoneAbstract:During pathogenic influenza virus infection, robust Cytokine production (Cytokine Storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P1R) signaling provided a chemically tractable approach for the effective blunting of Cytokine Storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P1R agonist treatment suppresses global Cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt Cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of Cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of Cytokine Storm. We identify the MyD88 adaptor molecule as responsible for the majority of Cytokine amplification observed following influenza virus challenge.
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Cytokine Storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine 1 phosphate agonist molecule
Current Topics in Microbiology and Immunology, 2014Co-Authors: Michael B A Oldstone, Hugh RosenAbstract:Cytokine Storm defines a dysregulation of and an excessively exaggerated immune response most often accompanying selected viral infections and several autoimmune diseases. Newly emerging and re-emerging infections of the respiratory tract, especially influenza, SARS, and hantavirus post considerable medical problems. Their morbidities and mortalities are often a direct result of Cytokine Storm. This chapter visits primarily influenza virus infection and resultant Cytokine Storm. It provides the compelling evidence that illuminates Cytokine Storm in influenza pathogenesis and the clear findings that Cytokine Storm is chemically tractable by therapy directed toward sphingosine-1-phosphate receptor (S1PR) modulation, specifically S1P1R agonist therapy. The mechanism(s) of how S1P1R signaling works and the pathways involved are subjects of this review.
Nicki Panoskaltsis - One of the best experts on this subject based on the ideXlab platform.
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Patients with gastrointestinal irritability after TGN1412-induced Cytokine Storm displayed selective expansion of gut-homing αβ and γδT cells
Cancer Immunology Immunotherapy, 2020Co-Authors: Neil E. Mccarthy, Andrew J. Stagg, Claire L. Price, Elizabeth R. Mann, Nichola L. Gellatly, Hafid O. Al-hassi, Stella C. Knight, Nicki PanoskaltsisAbstract:Following infusion of the anti-CD28 superagonist monoclonal antibody TGN1412, three of six previously healthy, young male recipients developed gastrointestinal irritability associated with increased expression of ‘gut-homing’ integrin β7 on peripheral blood αβT cells. This subset of patients with intestinal symptoms also displayed a striking and persistent expansion of putative Vδ2^+ γδT cells in the circulation which declined over a 2-year period following drug infusion, concordant with subsiding gut symptoms. These data demonstrate that TGN1412-induced gastrointestinal symptoms were associated with dysregulation of the ‘gut-homing’ pool of blood αβ and γδT cells, induced directly by the antibody and/or arising from the subsequent Cytokine Storm.
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Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced Cytokine Storm
Cancer Immunology Immunotherapy, 2020Co-Authors: Nicki Panoskaltsis, Neil E. Mccarthy, Andrew J. Stagg, Claire L. Price, Hafid O. Al-hassi, Catherine J. Mummery, Mariwan Husni, Naila Arebi, David Greenstein, Michalis KoutinasAbstract:Cytokine Storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from Cytokine Storm. After the initial Cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum Cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud’s phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8^+ T-cells were maintained at high levels, whereas naïve CD4^+ and memory CD4^+ and CD8^+ T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with Cytokine Storm.
Sonu Bhaskar - One of the best experts on this subject based on the ideXlab platform.
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Cytokine Storm in covid 19 immunopathological mechanisms clinical considerations and therapeutic approaches the reprogram consortium position paper
Frontiers in Immunology, 2020Co-Authors: Sonu Bhaskar, Akansha Sinha, Maciej Banach, Shikha Mittoo, Robert Weissert, Joseph S Kass, Santhosh Rajagopal, Anupama R Pai, Shelby KuttyAbstract:Cytokine Storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing Cytokine Storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, Cytokine Storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of Cytokine Storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the Cytokine Storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on Cytokine Storm from both a prognostic and therapeutic standpoint.
Hugh Rosen - One of the best experts on this subject based on the ideXlab platform.
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animal model of respiratory syncytial virus cd8 t cells cause a Cytokine Storm that is chemically tractable by sphingosine 1 phosphate 1 receptor agonist therapy
Journal of Virology, 2014Co-Authors: Kevin B Walsh, John R Teijaro, Hugh Rosen, Linda G Brock, Daniel M Fremgen, Peter L Collins, Michael B A OldstoneAbstract:The Cytokine Storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by Cytokine and immune cell components. The Cytokine Storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a Cytokine Storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8+ T cells infiltrated into the lung, initiating a Cytokine Storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited Cytokine Storm by blunting the PVM-specific CD8+ T cell response, resulting in diminished pulmonary disease and enhanced survival. IMPORTANCE A dysregulated overly exuberant immune response, termed a “Cytokine Storm,” accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the Cytokine Storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the Cytokine Storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these Cytokines with neutralizing antibodies blunts the Cytokine Storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
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mapping the innate signaling cascade essential for Cytokine Storm during influenza virus infection
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: John R Teijaro, Kevin B Walsh, Stephanie Rice, Hugh Rosen, Michael B A OldstoneAbstract:During pathogenic influenza virus infection, robust Cytokine production (Cytokine Storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P1R) signaling provided a chemically tractable approach for the effective blunting of Cytokine Storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P1R agonist treatment suppresses global Cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt Cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of Cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of Cytokine Storm. We identify the MyD88 adaptor molecule as responsible for the majority of Cytokine amplification observed following influenza virus challenge.
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Cytokine Storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine 1 phosphate agonist molecule
Current Topics in Microbiology and Immunology, 2014Co-Authors: Michael B A Oldstone, Hugh RosenAbstract:Cytokine Storm defines a dysregulation of and an excessively exaggerated immune response most often accompanying selected viral infections and several autoimmune diseases. Newly emerging and re-emerging infections of the respiratory tract, especially influenza, SARS, and hantavirus post considerable medical problems. Their morbidities and mortalities are often a direct result of Cytokine Storm. This chapter visits primarily influenza virus infection and resultant Cytokine Storm. It provides the compelling evidence that illuminates Cytokine Storm in influenza pathogenesis and the clear findings that Cytokine Storm is chemically tractable by therapy directed toward sphingosine-1-phosphate receptor (S1PR) modulation, specifically S1P1R agonist therapy. The mechanism(s) of how S1P1R signaling works and the pathways involved are subjects of this review.
Roberto Caricchio - One of the best experts on this subject based on the ideXlab platform.
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preliminary predictive criteria for covid 19 Cytokine Storm
Annals of the Rheumatic Diseases, 2021Co-Authors: Roberto Caricchio, Michael Bromberg, Marcello Gallucci, Chandra Dass, Xinyan Zhang, Stefania Gallucci, David Fleece, Gerard J CrinerAbstract:Objectives To develop predictive criteria for COVID-19-associated Cytokine Storm (CS), a severe hyperimmune response that results in organ damage in some patients infected with COVID-19. We hypothesised that criteria for inflammation and cell death would predict this type of CS. Methods We analysed 513 hospitalised patients who were positive for COVID-19 reverse transcriptase PCR and for ground-glass opacity by chest high-resolution CT. To achieve an early diagnosis, we analysed the laboratory results of the first 7 days of hospitalisation. We implemented logistic regression and principal component analysis to determine the predictive criteria. We used a ‘genetic algorithm’ to derive the cut-offs for each laboratory result. We validated the criteria with a second cohort of 258 patients. Results We found that the criteria for macrophage activation syndrome, haemophagocytic lymphohistiocytosis and the HScore did not identify the COVID-19 Cytokine Storm (COVID-CS). We developed new predictive criteria, with sensitivity and specificity of 0.85 and 0.80, respectively, comprising three clusters of laboratory results that involve (1) inflammation, (2) cell death and tissue damage, and (3) prerenal electrolyte imbalance. The criteria identified patients with longer hospitalisation and increased mortality. These results highlight the relevance of hyperinflammation and tissue damage in the COVID-CS. Conclusions We propose new early predictive criteria to identify the CS occurring in patients with COVID-19. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.
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etoposide as salvage therapy for Cytokine Storm due to coronavirus disease 2019
Chest, 2021Co-Authors: M Patel, Roberto Caricchio, Eduardo Dominguez, Daniel Sacher, Parag Desai, Ashwin Chandar, Michael Bromberg, Gerard J CrinerAbstract:Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality because of a lack of effective therapies. Therapeutic strategies under investigation target the overactive Cytokine response with anti-Cytokine or immunomodulators therapies. We present a unique case of severe Cytokine Storm resistant to multiple anti-Cytokine therapies, but eventually responsive to etoposide. Thus, etoposide may have a role as salvage therapy in treatment of Cytokine Storm in COVID-19. To our knowledge, this is the first reported case of use of etoposide in COVID-19.
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on the alert for Cytokine Storm immunopathology in covid 19
Arthritis & Rheumatism, 2020Co-Authors: Lauren A Henderson, Scott W Canna, Grant S Schulert, Stefano Volpi, Pui Y Lee, Kate F Kernan, Roberto Caricchio, Shawn A Mahmud, Melissa M Hazen, Olha HalyabarAbstract:Poor outcomes in COVID-19 correlate with clinical and laboratory features of Cytokine Storm syndrome. Broad screening for Cytokine Storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in Cytokine Storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.
