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Disruption of a Self-Amplifying Catecholamine Loop Reduces Cytokine Release Syndrome

Disruption of a Self-Amplifying Catecholamine Loop Reduces Cytokine Release Syndrome

Verena Staedtke, Ren-Yuan Bai, Kibem Kim, Martin Darvas, Marco L Davila, Gregory J Riggins, Paul B Rothman, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Shibin Zhou

Nature. 2018 Dec;564(7735):273-277.

PMID: 30542164

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP672877-A	Metyrosine		672-87-7	Price

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