scholarly journals Triggers, Timescales, and Treatments for Cytokine-Mediated Tissue Damage

2020 ◽  
Author(s):  
David McBride ◽  
Matthew Kerr ◽  
Nicholas Dorn ◽  
Dora Ogbonna ◽  
Evan Santos ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Cytokine Production ◽  
Viral Infections ◽  
Immune Dysregulation ◽  
Therapeutic Strategies ◽  
Cytokine Storm ◽  
T Cell Therapy ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Successes And Challenges

Inflammation, an essential cytokine-mediated process for generating a neutralising immune response against pathogens, is generally protective. However, aberrant or excessive production of proinflammatory cytokines is associated with uncontrolled local and systemic inflammation, resulting in cell death and often irreversible tissue damage. Uncontrolled inflammation can manifest over timescales spanning hours to years and is primarily dependent on the triggering event. Rapid and potentially lethal increases in cytokine production, or ‘cytokine storm’, develops in hours to days, and is associated with cancer cell-based immunotherapies, such as chimeric antigen receptor T-cell therapy. On the other hand, some bacterial and viral infections with high microbial replication or highly potent antigens elicit immune responses that result in supraphysiological systemic cytokine concentrations, which manifest over days to weeks. Immune dysregulation in autoimmune diseases can lead to chronic cytokine-mediated tissue damage spanning months to years, which often occurs episodically. Upregulation of IL-1, IL-6, IFN-γ, TNF, and granulocyte macrophage colony-stimulating factor frequently coincides with cytokine storm, sepsis, and autoimmune disease. Inhibition of proinflammatory molecules via antagonist monoclonal antibodies has improved clinical outcomes, but the complexity of the underlying immune dysregulation results in high variability. Rather than a ‘one size fits all’ treatment approach, an identification of disease endotypes may permit the development of effective therapeutic strategies that address the contributors of disease progression. Here, the authors present a literature review of the cytokine-associated aetiology of acute and chronic cytokine-mediated tissue damage, describe successes and challenges in developing clinical treatments, and highlight advancements in preclinical therapeutic strategies for mitigating pathological cytokine production.

scholarly journals Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1585
Author(s):  
Annamaria Paolini ◽  
Rebecca Borella ◽  
Sara De Biasi ◽  
Anita Neroni ◽  
Marco Mattioli ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Cells ◽  
Viral Infections ◽  
Virus Entry ◽  
Therapeutic Strategies ◽  
The Other ◽  
Cytokine Storm ◽  
Cytokines And Chemokines ◽  
Cell Death Mechanisms ◽  
The One

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.

scholarly journals Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

2021 ◽  
Vol 22 (23) ◽  
pp. 13009
Author(s):  
Xi-Dian Tang ◽  
Tian-Tian Ji ◽  
Jia-Rui Dong ◽  
Hao Feng ◽  
Feng-Qiang Chen ◽  
...  
Keyword(s):  
Immune System ◽  
Infectious Diseases ◽  
Targeted Therapies ◽  
Tissue Damage ◽  
Systemic Infection ◽  
Therapeutic Strategies ◽  
Targeted Treatment ◽  
Cytokine Storm ◽  
Pathophysiological Mechanisms ◽  
Circulating Cytokines

Cytokine storm is a phenomenon characterized by strong elevated circulating cytokines that most often occur after an overreactive immune system is activated by an acute systemic infection. A variety of cells participate in cytokine storm induction and progression, with profiles of cytokines released during cytokine storm varying from disease to disease. This review focuses on pathophysiological mechanisms underlying cytokine storm induction and progression induced by pathogenic invasive infectious diseases. Strategies for targeted treatment of various types of infection-induced cytokine storms are described from both host and pathogen perspectives. In summary, current studies indicate that cytokine storm-targeted therapies can effectively alleviate tissue damage while promoting the clearance of invading pathogens. Based on this premise, “multi-omics” immune system profiling should facilitate the development of more effective therapeutic strategies to alleviate cytokine storms caused by various diseases.

scholarly journals First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia

2020 ◽  
Author(s):  
Zelalem Temesgen ◽  
Mariam Assi ◽  
Paschalis Vergidis ◽  
Stacey A. Rizza ◽  
Philippe R. Bauer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Cells ◽  
Patient Characteristics ◽  
Cytokine Storm ◽  
Gm Csf ◽  
Cytokine Analysis ◽  
Single Use ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Poor Outcomes

ABSTRACTBackgroundIn COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe and critical COVID-19 pneumonia.MethodsHospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.ResultsTwelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe and critical COVID-19 pneumonia.ConclusionsIn high-risk COVID-19 patients with severe and critical pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.

Impaired Function of Fancc-/- Immune Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1494-1494
Author(s):  
Laura S. Haneline ◽  
Ying Liu
Keyword(s):  
Inflammatory Response ◽  
Peripheral Blood ◽  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Inflammatory Monocytes ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Immune Defects ◽  
Stimulating Factor

Abstract Abstract 1494 Fanconi anemia (FA) is a genetic disorder characterized by bone marrow (BM) failure, developmental defects and cancer predisposition. Previous studies suggest that FA patients exhibit alterations in immunologic function including high levels of pro-inflammatory cytokines and increased susceptibility to bacterial and viral infections. However, it is unclear whether the immune defects observed in FA patients are immune cell autonomous or secondary to leukopenia from evolving BM failure. The aim of the current study was to determine whether FA type C deficient (Fancc-/-) macrophage exhibit impaired function and contribute to an altered inflammatory response. In this study, primary macrophage function and the inflammatory response of Fancc-/- immune cells after in vivo intraperitoneal (IP) administration of lipopolysaccharide (LPS) was assessed. Adhesion of Fancc-/- peritoneal macrophages to LPS stimulated endothelial cells was reduced compared to WT (n=3, p<0.002). Phagocytosis of IgG–labelled latex beads (n=3, p<0.004) and E.coli (n=3, p<0.04) was also impaired in Fancc-/- peritoneal macrophages compared to WT. Given these in vitro data, we next assessed whether Fancc-/- macrophage would exhibit altered function after in vivo stimulation with LPS. A low dose of LPS (1mg/kg) was injected IP into Fancc-/- and WT mice to induce a local inflammatory response. Fancc-/- mice exhibited normal neutrophil recruitment to the peritoneum, though had decreased monocyte/macrophage recruitment during the resolution phase of inflammation (n=6, p<0.001). We next questioned whether altered cytokine and chemokine production may contribute to the reduced monocyte/macrophage recruitment observed in Fancc-/- mice. Two hours after LPS treatment, peritoneal cells from Fancc-/- mice had reduced TNF-α (n=3, p<0.05) and MIP-1α (n=3, p<0.02) mRNA expression. IL-6, IL-1β, KC, and MCP-1 showed a trend towards reduction in Fancc-/- cells, though was not statistically significant. Given the overall decrease in chemokine and cytokine production in Fancc-/- mice, we evaluated the peripheral blood for altered numbers of inflammatory monocytes (CD11b+F4/80+Ly-6Chigh) mobilized from the BM. LPS challenged Fancc-/- mice had a significant reduction in peripheral blood inflammatory monocytes 24 hours post LPS injection compared to WT (n=3, p<0.02). Previous published studies demonstrated that LPS stimulation of BM cells from WT mice results in expansion of monocyte/macrophage progenitors. Therefore, we questioned whether Fancc-/- BM cells exhibit altered expansion of monocyte/macrophage progenitors after in vivo LPS challenge. Colony formation in response to macrophage-colony stimulating factor (n=3, p<0.01) or granulocyte macrophage-colony stimulating factor (n=3, p<0.01) was decreased in Fancc-/- BM compared to WT after IP administration of LPS. Taken together these data suggest that the reduced replenishment of monocyte/macrophage in the local inflammatory site may be due to reduced chemokine/cytokine production, reduced mobilization of inflammatory monocytes in the peripheral blood, and decreased expansion of myeloid progenitors in the BM. Collectively, these data suggest that Fancc-/- macrophage exhibit cell autonomous immune defects. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Differential TLR7-mediated cytokine expression by R848 in M-CSF- versus GM-CSF-derived macrophages after LCMV infection

2020 ◽  
Author(s):  
Torki Alothaimeen ◽  
Evan Trus ◽  
Sameh Basta ◽  
Katrina Gee
Keyword(s):  
Cytokine Production ◽  
Lymphocytic Choriomeningitis ◽  
Cytokine Expression ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Csf Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Lcmv Infection

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) play an important role in macrophage (MФ) development by influencing their differentiation and polarization. Our goal was to explore the difference between M-CSF- and GM-CSF-derived bone marrow MФ responsiveness to TLR7-mediated signalling pathways that influence cytokine production early after infection in a model of acute virus infection. To do so, we examined cytokine production and TLR7-mediated signalling at 1 h post-lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) infection. We found that R848-induced cytokine expression was enhanced in these cells, with GM-CSF cells exhibiting higher proinflammatory cytokine expression and M-CSF cells exhibiting higher anti-inflammatory cytokine expression. However, R848-mediated signalling molecule activation was diminished in LCMV-infected M-CSF and GM-CSF macrophages. Interestingly, we observed that TLR7 expression was maintained during LCMV infection of M-CSF and GM-CSF cells. Moreover, TLR7 expression was significantly higher in M-CSF cells compared to GM-CSF cells. Taken together, our data demonstrate that although LCMV restrains early TLR7-mediated signalling, it primes differentiated MФ to enhance expression of their respective cytokine profiles and maintains levels of TLR7 expression early after infection.

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