β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD
Hemn Mohammadpour, Joseph L. Sarow, Cameron R. MacDonald, George L. Chen, Jingxin Qiu, Umesh C. Sharma, Xuefang Cao, Megan M. Herr, Theresa E. Hahn, Bruce R. Blazar, Elizabeth A. Repasky, Philip L. McCarthy
Hemn Mohammadpour, Joseph L. Sarow, Cameron R. MacDonald, George L. Chen, Jingxin Qiu, Umesh C. Sharma, Xuefang Cao, Megan M. Herr, Theresa E. Hahn, Bruce R. Blazar, Elizabeth A. Repasky, Philip L. McCarthy
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Research Article Immunology Transplantation

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

Abstract

Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of β2-AR–/– donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward Tregs rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor BM–derived myeloid-derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D+ effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.

Authors

Hemn Mohammadpour, Joseph L. Sarow, Cameron R. MacDonald, George L. Chen, Jingxin Qiu, Umesh C. Sharma, Xuefang Cao, Megan M. Herr, Theresa E. Hahn, Bruce R. Blazar, Elizabeth A. Repasky, Philip L. McCarthy

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Figure 5

The selective β2-AR agonist bambuterol increases the generation of donor BM-derived myeloid-derived suppressor cells (MDSCs).

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The selective β2-AR agonist bambuterol increases the generation of donor...
(A) CD11b+Gr-1+ (MDSC) frequencies within single live H-2b+H-2d–CD45+ populations from spleens and liver, 7 and 14 days after allo-HCT in the B6 → BALB/c model transplanted with 3.5 × 106 WT C57BL/6 TCD-BM combined with 0.7 × 106 WT C57BL/6 pan–T cells treated with daily saline and bambuterol injections. Data pooled from 2 individual experiments; total n = 5–6 per group. Bambuterol significantly increased MDSCs in spleen and liver compared with controls. (B) In vitro generation of BM MDSCs isolated from WT C57BL/6 mice in presence of terbutaline or terbutaline plus propranolol. Data pooled from 3 individual experiments, each with 2–3 replicates per group. Terbutaline significantly increased in vitro MDSC generation, which was blocked by propranolol. (C) In vitro generation of BM MDSCs isolated from WT or β2-AR–/– C57BL/6 mice in presence of terbutaline. Data pooled from 3 individual experiments, each with 2–3 replicates per group. Terbutaline significantly increased in vitro MDSC generation from WT but not β2-AR–/– BM. (D) Schematic design and MDSC generation from WT (CD45.1 H-2b) and β2-AR–/– (CD45.2 H-2b) TCD-BM gated on single live H-2d–CD3– cells. Lethally irradiated BALB/c mice were transplanted with 3.5 × 106 WT (CD45.1) and β2-AR–/– (CD45.2) C57BL/6 TCD-BM (50:50 ratios) combined with 0.7 × 106 WT (CD45.2) C57BL/6 pan–T cells. Recipients were treated with daily bambuterol injections. Data pooled from 2 individual experiments, each with n = 5 per group obtaining a total of n = 10 per group. At day 7 after allo-HCT, liver and spleen WT MDSC percentages were significantly higher compared with β2-AR–/–. For comparison of the means, an unpaired 2-tailed t test was used in A and D, and a 1-way ANOVA with Bonferroni’s post hoc test was used in B and C. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as median ± min to max.