| Autor: |
Ira Mellman, Siri Tahtinen, Leesun Kim, Ugur Sahin, Patricia Himmels, Yoko Oei, Andres Paler-Martinez, Jill Schartner, Emily C. Freund, Craig Blanchette, Weilan Ye, Benjamin Haley, Ann-Jay Tong, Sara Wichner, Cecile de la Cruz, Jaehak Oh, Mahesh Yadav, Mark McCarron, Lélia Delamarre, Zhainib Adel Amir |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Excessive systemic inflammation is characteristic to various acute conditions including sepsis, viral infections and immunotherapy-induced adverse events such as cytokine release syndrome (CRS). Recently, several clinical trials evaluating variants of lipid-formulated RNA vaccines for either cancer or COVID-19 have reported systemic inflammatory responses that limit vaccine dosing in humans. Preclinical studies in inbred laboratory mice failed to predict these adverse events, suggesting the existence of underlying differences in sensitivity to Toll-like receptor (TLR) or other innate agonists between humans and mice. Here, we identify interleukin 1 receptor antagonist (IL-1ra) as an endogenous, inducible suppressor of systemic inflammation. In humans, stimulation with a TLR7/8 adjuvanted RNA-lipoplex (RNA-LPX) vaccine results in the secretion of inflammasome-activated interleukin-1β (IL-1β) by monocytes. Remarkably, IL-1β was found to control the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6) associated with CRS. Unlike humans, murine leukocytes preferentially upregulate anti-inflammatory IL-1ra relative to IL-1β. IL-1ra deletion in mice leads to CRS-like symptoms, indicating that high levels of IL-1ra protect mice from uncontrolled systemic inflammation. Our results demonstrate that IL-1β and IL-1ra are key regulators that control systemic responses to RNA vaccines and other inflammatory stimuli. These data provide an explanation for the dramatic difference in dose-dependent tolerability between mice and humans and suggest an approach to evaluate pathogen-induced or immunotherapy-related inflammatory toxicities in vivo. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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