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

Research output: Contribution to journalLetter

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.

Original languageEnglish (US)
Pages (from-to)273-277
Number of pages5
JournalNature
Volume564
Issue number7735
DOIs
StatePublished - Dec 13 2018

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Catecholamines
Cytokines
T-Lymphocytes
alpha-Methyltyrosine
Bacteria
Reducing Agents
Tyrosine 3-Monooxygenase
Atrial Natriuretic Factor
Immunotherapy
Lipopolysaccharides
Macrophages
Antibodies
Therapeutics
Infection
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

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title = "Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome",
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.",
author = "Verena Staedtke and Renyuan Bai and Kibem Kim and Martin Darvas and Davila, {Marco L.} and Riggins, {Gregory J} and Rothman, {Paul B} and Nickolas Papadopoulos and Kinzler, {Kenneth W} and Bert Vogelstein and Shibin Zhou",
year = "2018",
month = "12",
day = "13",
doi = "10.1038/s41586-018-0774-y",
language = "English (US)",
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TY - JOUR

T1 - Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome

AU - Staedtke, Verena

AU - Bai, Renyuan

AU - Kim, Kibem

AU - Darvas, Martin

AU - Davila, Marco L.

AU - Riggins, Gregory J

AU - Rothman, Paul B

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W

AU - Vogelstein, Bert

AU - Zhou, Shibin

PY - 2018/12/13

Y1 - 2018/12/13

N2 - 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.

AB - 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.

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U2 - 10.1038/s41586-018-0774-y

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JF - Nature

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