Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling

Nicholas D. Leigh, Kathleen M. Kokolus, Rachel E. O'Neill, Wei Du, Jason W L Eng, Jingxin Qiu, George L. Chen, Philip L. McCarthy, J. David Farrar, Xuefang Cao, Elizabeth A. Repasky

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Abstract

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR2/2) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.

Original languageEnglish (US)
Pages (from-to)5045-5054
Number of pages10
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

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Graft vs Host Disease
Adrenergic Receptors
Temperature
Norepinephrine
Bone Marrow
Animal Care Committees
T-Lymphocytes
Adrenergic Agonists
Adrenergic Antagonists
Hematologic Diseases
Cell Transplantation
Immunosuppression
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Leigh, N. D., Kokolus, K. M., O'Neill, R. E., Du, W., Eng, J. W. L., Qiu, J., ... Repasky, E. A. (2015). Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling. Journal of Immunology, 195(10), 5045-5054. https://doi.org/10.4049/jimmunol.1500700

Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling. / Leigh, Nicholas D.; Kokolus, Kathleen M.; O'Neill, Rachel E.; Du, Wei; Eng, Jason W L; Qiu, Jingxin; Chen, George L.; McCarthy, Philip L.; Farrar, J. David; Cao, Xuefang; Repasky, Elizabeth A.

In: Journal of Immunology, Vol. 195, No. 10, 15.11.2015, p. 5045-5054.

Research output: Contribution to journalArticle

Leigh, ND, Kokolus, KM, O'Neill, RE, Du, W, Eng, JWL, Qiu, J, Chen, GL, McCarthy, PL, Farrar, JD, Cao, X & Repasky, EA 2015, 'Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling', Journal of Immunology, vol. 195, no. 10, pp. 5045-5054. https://doi.org/10.4049/jimmunol.1500700
Leigh, Nicholas D. ; Kokolus, Kathleen M. ; O'Neill, Rachel E. ; Du, Wei ; Eng, Jason W L ; Qiu, Jingxin ; Chen, George L. ; McCarthy, Philip L. ; Farrar, J. David ; Cao, Xuefang ; Repasky, Elizabeth A. / Housing temperature-induced stress is suppressing murine Graft-versus-host disease through β2-adrenergic receptor signaling. In: Journal of Immunology. 2015 ; Vol. 195, No. 10. pp. 5045-5054.
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AU - Qiu, Jingxin

AU - Chen, George L.

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