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Nature. 2018 Dec;564(7735):273-277. doi: 10.1038/s41586-018-0774-y. Epub 2018 Dec 12.

Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome.

Author information

1
Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. vstaedt1@jhmi.edu.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vstaedt1@jhmi.edu.
3
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rbai1@jhmi.edu.
4
Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
5
Department of Pathology, University of Washington, Seattle, WA, USA.
6
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
7
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. vogelbe@jhmi.edu.
10
Ludwig Center and the Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. sbzhou@jhmi.edu.

Abstract

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.

PMID:
30542164
DOI:
10.1038/s41586-018-0774-y

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