Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome
| Autor: | Bert Vogelstein, Ren Yuan Bai, Gregory J. Riggins, Paul B. Rothman, Nickolas Papadopoulos, Marco L. Davila, Verena Staedtke, Kibem Kim, Kenneth W. Kinzler, Shibin Zhou, Martin Darvas |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Multidisciplinary Tyrosine hydroxylase Lipopolysaccharide business.industry medicine.medical_treatment Metyrosine Immunotherapy Pharmacology medicine.disease Article 03 medical and health sciences chemistry.chemical_compound Cytokine release syndrome 030104 developmental biology Cytokine Atrial natriuretic peptide chemistry Catecholamine Medicine business medicine.drug |
| Popis: | 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. Atrial natriuretic peptide, an anti-inflammatory protein, can protect against cytokine release syndrome induced by therapeutic agents such as tumour-targeting bacteria and CAR-T cells by blocking catecholamine synthesis by macrophages. |
| Databáze: | OpenAIRE |
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