The NKT cell TCR repertoire can accommodate structural modifications to the lipid and orientation of the terminal carbohydrate of iGb3

Cameron, Garth; Cheng, Janice M. H.; Godfrey, Dale I.; Timmer, Mattie S. M.; Stocker, Bridget L.; Dangerfield, Emma M.

doi:10.1039/d2ra02373c

Cited by 2 publications

(1 citation statement)

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“…RA marketed as Lexiscan™ or Rapids-can™ is a coronary vasodilator that is used for myocardial perfusion imaging. A2AR agonists such as RA also suppress proinflammatory cytokine release from most immune cells and consequently produce a broader array of anti-inflammatory effects than drugs that target a single cytokine [12].…”

Section: Introductionmentioning

confidence: 99%

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

et al. 2023

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Background Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. Methods and findings Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4–5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). Conclusions Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

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Section: Introductionmentioning

confidence: 99%

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

et al. 2023

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Natural Killer T and Natural Killer Cell-Based Immunotherapy Strategies Targeting Cancer

et al. 2023

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Both natural killer T (NKT) and natural killer (NK) cells are innate cytotoxic lymphoid cells that produce inflammatory cytokines and chemokines, and their role in the innate immune response to tumors and microorganisms has been investigated. Especially, emerging evidence has revealed their status and function in the tumor microenvironment (TME) of tumor cells. Some bacteria producing NKT cell ligands have been identified to exert antitumor effects, even in the TME. By contrast, tumor-derived lipids or metabolites may reportedly suppress NKT and NK cells in situ. Since NKT and NK cells recognize stress-inducible molecules or inhibitory molecules on cancer cells, their status or function depends on the balance between inhibitory and activating receptor signals. As a recent strategy in cancer immunotherapy, the mobilization or restoration of endogenous NKT or NK cells by novel vaccines or therapies has become a focus of research. As a new biological evidence, after activation, effector memory-type NKT cells lasted in tumor-bearing models, and NK cell-based immune checkpoint inhibition potentiated the enhancement of NK cell cytotoxicity against cancer cells in preclinical and clinical trials. Furthermore, several new modalities based on the characteristics of NKT and NK cells, including artificial adjuvant vector cells, chimeric antigen receptor-expressing NK or NKT cell therapy, or their combination with immune checkpoint blockade have been developed. This review examines challenges and future directions for improving these therapies.

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The NKT cell TCR repertoire can accommodate structural modifications to the lipid and orientation of the terminal carbohydrate of iGb3

Abstract: The synthesised βG-iGb3 glycolipid, with a terminal 1,3-β linked galactose, induced NKT cell proliferation indicating that the α conformation of the terminal sugar residue of iGb3 is not essential for NKT cell TCR recognition.

Cited by 2 publications

References 47 publications

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies

Natural Killer T and Natural Killer Cell-Based Immunotherapy Strategies Targeting Cancer

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