Adrenergic stress is recognized to influence multiple arms of the immune system. Recent work in our lab supports the observation that conditions which cause physiologic stress (i.e., increase adrenergic stress) reduce T cell function. T cells are crucial mediators of graft versus host disease (GVHD), a common and often lethal side effect of allogeneic hematopoietic cell transplantation (allo-HCT). As many patients succumb to GVHD, being able to understand underlying factors that regulate its severity is paramount.
Our recent work led us to hypothesize that stress induced β-adrenergic receptor (AR) agonists such as norepinephrine may dampen GVHD following allo-HCT. To investigate the role of β-AR signaling on GVHD we performed MHC-mismatched allo-HCT in which recipient mice were treated with PBS (β-AR signaling intact) or a β-AR antagonist, propranolol, (i.e., a β-blocker) to inhibit β-AR signaling. Following allo-HCT, GVHD was significantly increased in mice treated with propranolol as evidenced by more weight loss (P<0.01) and decreased survival (P<0.01) compared to mice treated with PBS.
To confirm that the weight loss and decreased survival were indicative of T cell-mediated GVHD, we performed allo-HCT with T cell depleted bone marrow. No GVHD was observed in PBS- or propranolol-treated groups when the graft did not contain allogeneic T cells. Furthermore, syngeneic transplants also yielded no GVHD in PBS- or propranolol-treated groups. We next evaluated pathology in the liver, small and large intestine. We found that liver pathology was significantly increased (P<0.05) in mice treated with propranolol compared to the PBS treated group. Thus, for the first time we have found that the level of systemic β-AR-mediated stress signaling regulates the severity of GVHD.
We next asked whether we could regulate GVHD by manipulating endogenous levels of the β-AR agonist, norepinephrine, by exposing mice to physiological stress. To test this we used mildly cool housing temperature to activate the adrenergic stress response as temperature manipulation is a classic means to study norepinephrine-driven stress signaling. We housed mice at 22°C, a temperature in which mice are cold stressed, and 30°C, a temperature in which the adrenergic stress response is significantly reduced. Therefore in this model, we predicted that GVHD would be reduced in severity in mice housed at 22°C compared to those housed at 30°C.
We first confirmed that mice housed at 22°C were more stressed by measuring norepinephrine levels, finding that norepinephrine was significantly elevated both pre- and 13 days post-allo-HCT (P<0.05). As predicted, cold stressed mice housed at 22°C had significantly less GVHD as evidenced by reduced weight loss (P<0.01), improved survival (P<0.01), and less liver pathology (P<0.05) when compared to mice housed at 30°C. This strongly supports our results obtained using pharmacological inhibition of β-AR signaling. At 30°C, there is minimal norepinephrine-driven stress, and therefore is not surprising that propranolol treatment of these mice had no effect on the severity of GVHD. Thus, these findings suggest that allogeneic graft vs. host responses were responsible for weight loss and decreased survival in conditions in which adrenergic stress was alleviated (housing at 30°C) or the stress response was blocked (treatment with propranolol). Therefore β-AR signaling plays a vital and previously unrecognized role in modulating the severity of GVHD.
Clinically, using β-blockers to achieve pharmacologic inhibition of β-AR signaling is commonly used to alleviate symptoms of hypertension or other age-related diseases in elderly patients. Of note, β-blockers are also routinely given post allo-HCT to ameliorate symptoms such as hypertension and tachycardia. Thus, following allo-HCT, it may be important to reconsider the use of β-blockers as our findings suggest that the degree of β-AR signaling regulates the severity of GVHD.
Citation Format: Nicholas D. Leigh, Kathleen M. Kokolus, Jason W-L Eng, Jingxin Qiu, George L. Chen, Philip L. McCarthy, Xuefang Cao, Elizabeth A. Repasky. The degree of adrenergic stress signaling regulates the severity of graft versus host disease following allogeneic hematopoietic cell transplantation. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B43.
- ©2015 American Association for Cancer Research.