PMC:7546716 / 31357-47226 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7546716","sourcedb":"PMC","sourceid":"7546716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7546716","text":"Implications for therapy\nAlthough more conclusive results are awaited from randomised controlled trials, encouraging preliminary results have been reported for the successful management of severe and critical COVID-19 by therapeutic modulation of IL-1α and IL-1β with recombinant IL-1RA (anakinra)84, 85 and by blocking GM-CSF using monoclonal antibodies (mavrilimumab, lenzilumab).86, 87 Although some studies have shown that IL-6 peaks at advanced stages of COVID-19 and is associated with disease severity,2, 10, 15 other studies have reported conflicting data on IL-6 and IL-6 receptor expression in patients,9, 11 and the results with anti-IL-6 receptor antibodies (eg, tocilizumab, sarilumab) have been controversial.88, 89, 90\nTargeting IL-33 (eg, by using anti-ST2 antibodies such as astegolimab), could be the key for controlling excessive lung inflammation. In a mouse model of influenza virus-induced asthma exacerbation,58 administration of an anti-ST2 antibody significantly reduced airway hyper-responsiveness and bodyweight loss, lowered inflammatory cell numbers in the lungs, and eliminated neutrophil extracellular traps in the airway lumen; moreover, anti-ST2 treatment restored lung expression of IFNβ, IL-12p35, and IL-12p70, and reduced viral load.58 There are several ongoing phase 2 trials using anti-ST2 therapy for inflammatory lung diseases such as chronic obstructive pulmonary disease and asthma.12 In the IFNγ-deficient mouse model of atypical MAS, blocking ST2 provided significant protection against weight loss, increased survival, reduced serum ferritin and soluble CD25 concentrations, and lowered CD8+ T-cell frequencies and neutrophilia.32 By contrast, individually blocking IL-6, IL-1β, or GM-CSF did not provide major protection against disease, suggesting that dampening IL-33–ST2 signalling, rather than individual downstream effector cytokines, might be more effective in treating either canonical MAS or atypical MAS-like diseases,32 such as COVID-19.2 A study evaluating the safety and efficacy of astegolimab (MSTT1041A) in severe COVID-19 pneumonia is recruiting participants (NCT04386616; EudraCT 2020-002713-17). The anti-IL-33 monoclonal antibody, MEDI3506, has also been included among possible therapies for the treatment of hospitalised patients with COVID-19 and is currently being tested in a phase 2 adaptive platform study.91\nAdditional important cell targets to focus on include ILC2, IL-17-producing and GM-CSF-producing γδT17 cells, proinflammatory monocytes–macrophages, extracellular trap-producing neutrophils, and mast cells. Different strategies could be set up to control aberrant activation of these cells, for instance by targeting IL-9 (MEDI-528), Vγ9Vδ2 T-cell activation (pentoxifylline),74 IL-17A, IL-17F, and IL-17E (bimekizumab, brodalumab),92 and cytokine balance (using colchicine,93 NLRP3 inhibitors,94 TLR2 inhibitors,95 JAK2 inhibitors,96 apremilast,97 mast cells stabilisers,55 and vitamin D).98\nActing more directly on the T-cell homing by using anti-CCR5 (leronlimab),99 anti-CCR2 (prozalizumab), CCR2 and CCR5 inhibitors (BMS-813160), anti-CCL2 (carlumab), or anti-CCL8 antibodies, might be another crucial strategy in the management of patients with COVID-19. Additionally, anti-CCR1 (AZD4818) and anti-CXCR2 (AZD5069) antibodies, which selectively act on recruitment of monocytes and neutrophils, might be considered for patients at advanced stages of disease. In patients with post-acute respiratory distress syndrome, diverse antifibrotic agents acting on TGFβ (fresolimumab, pirfenidone), IL-13 (lebrikizumab, dupilumab),100 connective tissue growth factor (pamrevlumab), fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor signalling (nintedanib),79 might all represent viable therapeutic options (figure 3 , table ).\nFigure 3 Inflammatory patterns in COVID-19 at various disease stages\nCytokine interplay between IL-33, GM-CSF, IL-1α, and IL-1β, and key cytokines, chemokines, and receptors, the composition of lung inflammatory infiltrates, cell phenotypes involved, and possible therapeutic options according to different stages of disease. CCR=C-C motif chemokine receptor. CCL=C-C motif chemokine ligand. CXCL=C-X-C motif chemokine. CXCR=C-X-C motif chemokine receptor. FABP=fatty acid-binding protein. FCN=ficolin. FGF=fibroblast growth factors. GATA=GATA-binding factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. i=inhibitor. IFN=interferon. IL=interleukin. ILC2=type 2 innate lymphoid cell. JAK=Janus kinase. NLRP=NACHT, LRR, and PYD domains-containing protein. PDGF=platelet-derived growth factor. PDGF-Ri=platelet-derived growth factor receptor inhibitor. rIL=recombinant interleukin. SPP=secreted phosphoprotein. sST2= soluble ST2. ST2=ST2 receptor. TGF=transforming growth factor. Th=T-helper. TLR=toll-like receptor. Treg=regulatory T cell. VEGF=vascular endothelial growth factor.\nTable Advantages and disadvantages of various drugs for COVID-19\nMolecular targets Cell targets Advantages Disadvantages\nAnti-ST2 (eg, astegolimab), anti-IL-33 (eg, MEDI-3506), small-molecule ST2 inhibitors IL-33-ST2 axis, soluble ST2 GATA3+ regulatory T cells, ILC2, type 2 pneumocytes, IL-2 and IL-7-producing dendritic cells, IL-9 and IL-7-driven γδT17 cells, GM-CSF-producing T cells, neutrophils, endothelial cells, mast cells, and M2 macrophages Effective against virus-induced exacerbations of asthma, might restore antiviral interferon responses; effective in haemophagocytic lymphohistiocytosis and MAS-like models incorporating interferon deficiencies (resembling severe–critical COVID-19); might be effective at all stages of COVID-19; and has potential against obesity-related severe COVID-19 Complexity of IL-33 biology—eg, nuclear versus extracellular cytokine, full-length versus cleaved form, membrane versus soluble receptor (targeting ST2 over IL-33 seems safer); atheroprotective and cardioprotective roles hypothesised for IL-33; unclear whether suppression of proinflammatory Th1 and Th17 cells by anti-ST2 favours Th2 responses along with regulatory T cell expansion; however, inhibition of ILC2, M2 and type 2 pneumocytes should overall result in antifibrotic effects\nAnti-GM-CSF (eg, mavrilimumab, gimsilumab, lenzilumab, otilimab) GM-CSF Type 2 pneumocytes, monocytes, macrophages, neutrophils, endothelial cells Encouraging preliminary data in severe-to-critical COVID-19 and good safety Might be less effective at earlier stages; possibly interferes with alveolar macrophage homoeostasis and alveolar surfactant production\nRecombinant IL-1RA (eg, anakinra), anti-IL-1β (eg, canakinumab), recombinant IL-37 IL-1α and IL-1β, or IL-1β Type-2 pneumocytes, GM-CSF-producing γδT and Th17 cells, monocytes, macrophages, neutrophils, endothelial cells, adipocytes Encouraging preliminary data in severe–critical COVID-19; potential against obesity-related severe forms of COVID-19; good safety (short half-life of anakinra) Might be less effective at earlier stages\nRecombinant IL-36RA or IL-38 IL-36 cytokines T cells, mast cells, neutrophils, monocytes, macrophages, endothelial cells, fibroblasts IL-36α promotes influenza virus-induced lung injury and mortality IL-36β supports antiviral interferon responses; IL-36γ supports alveolar macrophage survival during viral infection\nAnti-IL-6 receptor (eg, tocilizumab, sarilumab), anti-IL-6 (eg, clazakizumab, siltuximab) IL-6 Natural killer cells, T cells, B cells, endothelial cells Might help restore suppressed natural killer cell functions and oppose acute respiratory distress syndrome development IL-6 might have homoeostatic roles and induce SOCS3, IL-4Rα and CD163; conflicting preliminary results in severe–critical COVID-19; might favour bacterial, viral, and opportunistic infections (long half-life of IL-6 inhibitors)\nAnti-IFNγ (eg, emapalumab) IFNγ Macrophages, dendritic cells, B cells, T cells, endothelial cells Might inhibit macrophage hyperactivation and induction of CXCL9 and CXCL10; might partly inhibit pathogenicity of effector T cells coexpressing GM-CSF and IFNγ Exogenous IFNγ inhibited the expression of GM-CSF by CD8+ T cells in haemophagocytic lymphohistiocytosis and MAS-like models with IFNγ deficiency; and anti-IFNγ might dampen protective antiviral cytotoxic T lymphocytes and B-cell responses orchestrated by interferons and Th1 cells\nAntimalarials (eg, chloroquine, hydroxychloroquine) Endosomal toll-like receptors Dendritic cells, monocytes, macrophages, neutrophils, B cells, pneumocytes Might inhibit virus entry in vitro Possibly dampen endosomal toll-like receptor-induced, TRIF-mediated, protective, type 1 interferon signalling; possible cardiotoxicity\nType 3 interferons (eg, peg-interferon lambda-1, or recombinant IL-29) Anti-viral immune responses Pneumocytes (tissue-barrier epithelial cells), dendritic cells, macrophages, neutrophils IFNλ might overcome suppression of interferons and stimulate antiviral immune responses without detrimental hyperinflammation (restricted expression pattern of IFNλ receptor 1); less inflammatory side-effects than IFNα in patients with hepatitis C virus and in influenza-infected mice Knowledge of interferon lambda biology in humans is incomplete\nHeparins (and small molecule toll-like receptor 2 inhibitors) Virus interaction with heparan sulphate on cell membranes Virus-susceptible host cells Possibly block coronavirus-induced, toll-like receptor 2-mediated, TNF and IL-6 production; might inhibit virus entry; and have antithrombotic effects Effective dose and best route of administration are unclear; risk of bleeding\nAnti-IL-4Rα (eg, dupilumab), anti-IL-13 (eg, lebrikizumab) IL-4 and IL-13, or IL-13 M2 macrophages, ILC2, Th2 cells, mast cells, eosinophils, B cells, myofibroblasts Might inhibit virus-induced asthma exacerbations; and have a potential benefit in pulmonary fibrosis Possible exacerbation of Th17 responses and neutrophilia in severe–critical COVID-19\nAnti-IL-9 (eg, MEDI-528) IL-9 ILC2, γδT17 cells, effector memory T cells, neutrophils, mast cells, M2 macrophages Might inhibit expansion of lymphoid cells, mast cell activation, and neutrophil recruitment in COVID-19 pneumonia; and might inhibit production of TGFβ and pulmonary fibrosis Might favour proinflammatory activation of monocytes and macrophages\nAnti-IL-17A and anti-IL-17F (eg, bimekizumab), anti-IL-17RA (eg, brodalumab) IL-17A, IL-17F, IL-17E (or IL-25) Neutrophils, monocytes, macrophages, mast cells, endothelial cells, fibroblasts, ILC2 Might inhibit neutrophil recruitment and detrimental inflammation in severe COVID-19; and by acting on IL-25, brodalumab could also inhibit ILC2 differentiation Might favour fungal and bacterial infections\nSelective JAK2 inhibitors (eg, fedratinib) IL-23, IL-6 γδT17 cells, Th17, GM-CSF-producing T cells, mast cells, neutrophils Possibly inhibit inflammation in severe COVID-19 and do not interfere with JAK1-dependent interferon signalling Do not interfere with IL-9, IL-2, and IL-7-mediated expansion of effector T cells; might favour bacterial, viral, and opportunistic infections\nAnti-CCR2 (eg, prozalizumab), anti-CCR5 (eg, leronlimab), dual CCR2 and CCR5-inhibitors (eg, BMS-813160) CCR2 or CCR5, or both γδT17 cells, GM-CSF-producing T cells, monocytes, macrophages Might inhibit homing of mononuclear cells; encouraging data have been shown for leronlimab on restoration of immune functions in COVID-19 and clinical improvement; good safety Redundancy and complexity of the chemokine receptor system; several compounds targeting CCR2 or CCR5 did not show clinical efficacy as presumed from preclinical models\nAnti-CCL2 (eg, carlumab), anti-CCL8 CCL2 or CCL8 γδT17 cells, T cells, monocytes, macrophages, neutrophils, fibroblasts Possibly act on different stages of COVID-19 Use of carlumab was unsuccessful in idiopathic pulmonary fibrosis\nAnti-CCR1 (eg, AZD4818), anti-CXCR2 (eg, AZD5069) CCR1 or CXCR2 Monocytes, macrophages, neutrophils Possibly inhibit tissue recruitment of monocytes and neutrophils Use of these drugs was unsuccessful in chronic obstructive pulmonary disease and asthma\nColchicine Tubulin (cytoskeleton) Monocytes, macrophages, pneumocytes, neutrophils, endothelial cells, platelets Might inhibit NLRP3 assembly, neutrophil recruitment, and platelet aggregation; has antiviral properties Use of colchicine was unsuccessful in idiopathic pulmonary fibrosis; frequent diarrhoea\nNLRP3 inflammasome inhibitors (eg, dapansutrile, CP-456773) NLRP3 Macrophages and other cells Shown to inhibit caspase-1, thereby preventing activation of IL-1β and IL-18; effective in murine models of pulmonary inflammation; and have a potential benefit in heart failure Might be less effective at earlier stages\nNon-selective phosphodiesterase inhibitors (eg, pentoxifylline) Phosphodiesterases (adenosine receptor A2A-dependent mechanisms) γδ T cells, alveolar macrophages, mast cells, neutrophils, endothelial cells, platelets Might inhibit proinflammatory Vγ9Vδ2 T cells and TNF release; anti-inflammatory effects in experimental acute lung injury; haemorheological and antithrombotic properties; broad-spectrum antiviral activity Risk of bleeding\nPhosphodiesterase-4 inhibitors (eg, apremilast) Phosphodiesterase-4 (enhanced by adenosine receptor A2A agonists) Monocytes, macrophages, dendritic cells, T cells, fibroblasts Possibly inhibit production of CXCL10, interferon gamma, IL-23, TNF, and leucocyte infiltration; ameliorate pulmonary inflammation in experimental models Frequent diarrhoea\nMast cell stabilisers (eg, sodium cromoglycate, ketotifen) Ion (calcium) channels, histamine receptor H1 Mast cells Might act on several symptomatic and pathogenic aspects of COVID-19 Might cause sedation, possibly favouring respiratory depression\nVitamin D Vitamin D response elements Regulatory T cells, effector T cells, dendritic cells, adipocytes, mast cells Possibly shifts the T cell balance in favour of regulatory T cells rather than Th9 and Th17; might inhibit Vγ9Vδ2 T cells and adipocyte release of CCL2, and stabilise mast cells Appropriate dosage for use as an immunomodulant is not defined; potential toxicity linked to hypercalcaemia\nAnti-(pan)TGFβ (eg, fresolimumab) TGFβ(2) ILC2, IL-9, and IL-17- producing T cells, M2 macrophages, fibroblasts, pneumocytes Might act on different stages of COVID-19; might inhibit ST2 upregulation and IL-9 production; and has a potential benefit in pulmonary fibrosis Might inhibit regulatory T cell activity\nAnti-connective tissue growth factor (eg, pamrevlumab) CTGF, TGFβ pathway Fibroblasts, pericytes, endothelial cells, cardiomyocytes Potential benefit in pulmonary fibrosis Might be effective only at later stages\nReceptor tyrosine kinase inhibitors (eg, nintedanib) Vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor receptors Fibroblasts, pericytes, endothelial cells, cardiomyocytes Approved for treating pulmonary fibrosis Might be effective only at later stages and correct timing is unclear; frequent diarrhoea; risk of bleeding\nPirfenidone TGFβ pathway M2 macrophages, fibroblasts Approved for treating pulmonary fibrosis Might be effective only at later stages\nA2A=adenosine 2A. CCR=C-C motif chemokine receptor. CCL=C-C motif chemokine ligand. CTGF=connective tissue growth factor. CXCL=C-X-C motif chemokine. CXCR=C-X-C motif chemokine receptor. GATA=GATA-binding factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. H1 receptor=histamine receptor. IFN=interferon. IL=interleukin. ILC2=type 2 innate lymphoid cells. JAK=Janus kinase. MAS=macrophage activation syndrome. NLRP=NACHT, LRR, and PYD domains-containing protein. SOCS=suppressor of cytokine signalling. ST2=ST2 receptor. TGF=transforming growth factor. Th=T-helper. TNF=tumour necrosis factor. 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