β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Abstract

warmer, thermoneutral temperature (TT). Housing mice at TT substantially reduces norepinephrine and β-AR signaling on immune cells (22). Treatment of allo-HCT mice housed at ST with the pan-beta blocker propranolol increased aGvHD severity, indicating that β-AR signaling is protective against aGvHD (22). Furthermore, we demonstrated that blockade of recipient β2-ARs enhanced the GvT effect by modulating antigen presenting cells (23). It was critical to continue to define the role of T cell β2-AR signaling, especially CD4 + T cell differentiation. In addition, the detailed mechanisms of β2-AR signaling and its downstream effects on immunomodulation after allo-HCT remained incompletely understood.Adrenergic receptors (ARs) are G protein-coupled receptors, classified into 2 general classes: α-ARs and β-ARs. The α1-AR is primarily expressed on endothelial cells, and the α2-AR is more ubiquitously expressed. β1-ARs and β3-ARs are primarily expressed in cardiac and adipose tissues, respectively, while β2-ARs are extensively distributed especially in the respiratory tract (24, 25) and on immune cells (26,27). Emerging studies reinforce an inhibitory role of β2-AR signaling on T cell function, especially CD8 + T cells, in preclinical and clinical tumor models (27,28). The β2-AR is activated by catecholamines (norepinephrine and epinephrine), released by the sympathetic nervous system (27, 29) and splenic tyrosine hydroxylase-expressing cells (30). This β2-AR-mediated regulation affects T cell antitumor functions (28), DC antigen presentation (23), B cell expression of costimulatory molecules (31, 32), and myeloid-derived suppressor cell (MDSC) immunosuppression ( 26).Thus, we focused on the role of β2-AR signaling on immune cell development and pathways during aGvHD. We asked whether β2-AR expression by allogeneic donor T cells modulates aGvHD pathology and how this modulation occurs. Using major histocompatibility complex (MHC) and minor histocompatibility antigen (miHA) mismatched HCT murine models, and a humanized NOD-scid IL-2Rγ -/-(NSG) model of aGvHD, we demonstrate that β2-AR expression by allogeneic T cells regulates the differentiation of CD4 + T cells from Th1/Th17 to a Th2/Treg phenotype, ameliorating aGvHD without compromising GvT. These data lead us to propose that selective β2-AR agonists may serve as potential therapeutic agents to attenuate aGvHD while preserving the GvT effect.

Pharmacological modulation of myeloid-derived suppressor cells to dampen inflammation

“…Recently, one promising approach in endogenous MDSC generation was achieved with the help of β 2 -AR agonists in a murine model of GVHD ( 52 ). Treatment with bambuterol – a prodrug of the selective β 2 -agonist terbutaline – significantly increased the number of MDSCs and Tregs while effector T cells were reduced and GVHD was ameliorated ( 52 ). All other mechanisms of action were excluded, and the central role of β 2 -AR was confirmed ( 52 ).…”

“…Treatment with bambuterol – a prodrug of the selective β 2 -agonist terbutaline – significantly increased the number of MDSCs and Tregs while effector T cells were reduced and GVHD was ameliorated ( 52 ). All other mechanisms of action were excluded, and the central role of β 2 -AR was confirmed ( 52 ). Accordingly, in vitro cultivation of MDSCs is also increased by terbutaline ( 52 ).…”

“…All other mechanisms of action were excluded, and the central role of β 2 -AR was confirmed ( 52 ). Accordingly, in vitro cultivation of MDSCs is also increased by terbutaline ( 52 ). Terbutaline and other β 2 -agonists are used to treat asthma or COPD due to their bronchodilator effect.…”

Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery

“…A recent study by Mohammadpour et al extended these findings using different models of allogeneic and xenogeneic models of HSCT. They found that adoptive transfer of allogeneic, β2-AR deficient (β2-AR −/− ) CD4 + T cells (with BM) into lethally irradiated recipients induced more severe aGVHD than did engraftment with wild type (WT) allogeneic T cells [139]. The exacerbation of disease in mice engrafted with β2-AR −/− CD4 + T cells was associated with increased numbers Th1 effector cells whereas transfer of WT T cells resulted in increases in Tregs, Th2 cells and myeloid derived suppressor cells [139].…”

Manipulating adrenergic stress receptor signaling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants

“… 30 , 31 , 32 , 33 , 34 The strong, naturally occurring immunosuppressive potential of β‐AR signalling is consistent with our observations that adrenergic stress or addition of β‐AR agonists can suppress graft versus host disease (GVHD) following allogeneic bone marrow transplantation (BMT). 34 , 35 , 36 …”