Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.650295
Keywords
hyperinflammatory syndromes; cytokine release syndrome; cytokine storm syndrome; hemophagocytic lymphohistiocytosis; JAK inhibition
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Funding
- Incyte Corporation
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Hyperinflammatory syndromes are characterized by severe inflammation, multiple organ dysfunction, and potential death. Oral ruxolitinib dosing effectively reduces the harmful consequences of immune overactivation in various hyperinflammatory models without causing broad immunosuppression.
Hyperinflammatory syndromes comprise a heterogeneous group of disorders characterized by severe inflammation, multiple organ dysfunction, and potentially death. In response to antigenic stimulus (e.g., SARS-CoV-2 infection), overactivated CD8+ T-cells and macrophages produce high levels of proinflammatory cytokines, such as IFN-gamma, TNF-alpha, IL-6, and IL-12. Multiple inflammatory mediators implicated in hyperinflammatory syndromes utilize the Janus kinase-signal transducers and activators of transcription (JAK-STAT) cascade to propagate their biological function. Our findings demonstrate that oral ruxolitinib dosing designed to mimic clinically relevant JAK-STAT pathway inhibition significantly reduces the harmful consequences of immune overactivation in multiple hyperinflammatory models. In contrast to monoclonal antibody therapies targeting a single cytokine, ruxolitinib effectively downregulates the functional effect of multiple cytokines implicated in hyperinflammatory states, without broad immunosuppression.
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