Graft-versus-host disease (GVHD) is a common and serious complication after allogeneic hematopoietic cell transplantation (allo-HCT), while the closely related graft-versus-leukemia/lymphoma (GVL) effect is crucial for the effectiveness of allo-HCT for blood cancer patients. Adrenergic stress signaling mediated through ?- adrenergic receptor (AR) agonists such as norepinephrine is recognized to influence both innate and adaptive immunity. To investigate the previously unknown role of ?-AR signaling in GVHD, we used murine models to perform allo-HCT in which recipient mice were treated with specific ?-AR antagonists or agonists. Our findings show that agonistic stimulation of ?2-AR signaling significantly decreased GVHD while blocking of ?2-AR signaling significantly increased GVHD. We have also found that manipulating endogenous levels of norepinephrine, by exposing mice to a physiological stress (i.e. mild cold stress) completely recapitulates the findings obtained using pharmacologic manipulation of ?-AR signaling. Based on these findings, we hypothesize that stress-induced ?2-adrenergic signaling may control GVH and GVL responses via regulating the functions of donor-derived T cell subsets. Importantly, these findings suggest that manipulation of ?2-AR signaling is a feasible and immediately testable strategy to improve the effectiveness of allo-HCT. Therefore, we will study HCT patients and murine models to pursue three aims.
Aim 1 will examine norepinephrine blood levels in allo-HCT patients as a potential factor influencing clinical outcomes. We will study about 200 de- identified patients to analyze the relationship between ?-adrenergic signaling levels and clinical outcomes including GVHD incidence, severity and cancer relapse.
Aim 2 will evaluate the therapeutic potential of manipulating ?-AR signaling to modulate GVH and GVL responses. We have recently established a xenotransplantation system using humanized NSG mice as hosts to examine the GVH and GVL functions of human immune cells. We will use this new translational platform to evaluate the impact of manipulating ?-AR signaling on the GVH and GVL activities of human T cells.
Aim 3 will explore T cell-dependent mechanisms by which ?2-AR signaling impacts GVH and GVL responses. We will use ?2-AR deficient mice as donors to determine how ?2-AR signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD and to mediate the favorable GVL effect. In summary, this project will not only improve our understanding of the basic biology of allo-HCT, but it may also help to explain why patients, who naturally exhibit widely differing stress responses, differ so widely in terms of their development of GVHD or cancer remission. Moreover, this research may lead to a completely new therapeutic rationale based upon manipulation of ?-AR signaling for the prevention of GVHD and preservation of the beneficial GVL effect.

Public Health Relevance

Graft-versus-host disease (GVHD) is a common and serious complication after allogeneic hematopoietic cell transplantation (allo-HCT), while the closely related graft-versus-leukemia/lymphoma (GVL) effect is crucial for the effectiveness of allo-HCT for blood cancer patients. Using established murine models, we have discovered that pharmacologic or physiologic manipulation of ?-adrenergic receptor signaling exhibits a significant impact on GVHD incidence and severity. In this project, we will study the clinical relevance, therapeutic potential and cellular mechanisms by which ?-adrenergic receptor signaling impacts GVHD and GVL effect.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21CA202358-03
Application #
9615578
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Salomon, Rachelle
Project Start
2017-12-16
Project End
2019-06-30
Budget Start
2017-12-16
Budget End
2019-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Mohammadpour, Hemn; O'Neil, Rachel; Qiu, Jingxin et al. (2018) Blockade of Host ?2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs. J Immunol 200:2479-2488
Leigh, Nicholas D; O'Neill, Rachel E; Du, Wei et al. (2017) Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function. J Immunol 199:336-347
Bian, Guanglin; Leigh, Nicholas D; Du, Wei et al. (2016) Interferon-Gamma Receptor Signaling Plays an Important Role in Restraining Murine Ovarian Tumor Progression. J Immunol Res Ther 1:15-21