Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through beta(2)-Adrenergic Receptor Signaling

作者：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

来源：The Journal of Immunology, 2015, 195(10): 5045-5054.

DOI：10.4049/jimmunol.1500700

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 (similar to 22 degrees C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (similar to 30 degrees C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through beta-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22 degrees C with a beta(2)-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30 degrees C. Conversely, administering a beta(2)-adrenergic agonist decreases GVHD in mice housed at 30 degrees C. In further mechanistic studies using beta(2)-adrenergic receptor-deficient (beta(2)-AR(-/-)) mice, we found that it is host cell beta(2)-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of beta-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of beta(2)-AR signaling to ameliorate GVHD in the clinical setting.

• 出版日期2015-11-15