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An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

ABSTRACT: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics.

SUBMITTER: Futch HS

PROVIDER: S-EPMC6829597 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

Futch Hunter S HS McFarland Karen N KN Moore Brenda D BD Kuhn M Zino MZ Giasson Benoit I BI Ladd Thomas B TB Scott Karen A KA Shapiro Melanie R MR Nosacka Rachel L RL Goodwin Marshall S MS Ran Yong Y Cruz Pedro E PE Ryu Daniel H DH Croft Cara L CL Levites Yona Y Janus Christopher C Chakrabarty Paramita P Judge Andrew R AR Brusko Todd M TM de Kloet Annette D AD Krause Eric G EG Golde Todd E TE

The Journal of experimental medicine 20190829 11

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously r ...[more]

PMID: 31467037

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Project description:BACKGROUND: Laboratory routine procedures such as handling, injection, gavage or transportation are stressful events which may influence physiological parameters of laboratory animals and may interfere with the interpretation of the experimental results. Here, we investigated if female BALB/c mice derived from in-house breeding and BALB/c mice from a vendor which were shipped during their juvenile life differ in their HPA axis activity and stress responsiveness in adulthood. RESULTS: We show that already transferring the home cage to another room is a stressful event which causes an increased HPA axis activation for at least 24 hours as well as a loss of circulating lymphocytes which normalizes during a few days after transportation. However and important for the interpretation of experimental data, commercially available strain-, age- and gender-matched animals that were shipped over-night showed elevated glucocorticoid levels for up to three weeks after shipment, indicating a heightened HPA axis activation and they gained less body weight during adolescence. Four weeks after shipment, these vendor-derived mice showed increased corticosterone levels at 45-min after intraperitoneal ACTH challenge but, unexpectedly, no acute stress-induced glucocorticoid release. Surprisingly, activation of monoaminergic pathways were identified to inhibit the central nervous HPA axis activation in the vendor-derived, shipped animals since depletion of monoamines by reserpine treatment could restore the stress-induced HPA axis response during acute stress. CONCLUSIONS: In-house bred and vendor-derived BALB/c mice show a different stress-induced HPA axis response in adulthood which seems to be associated with different central monoaminergic pathway activity. The stress of shipment itself and/or differences in raising conditions, therefore, can cause the development of different stress response phenotypes which needs to be taken into account when interpreting experimental data.

Dataset Information

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

Publications

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

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