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 1

Expression of β2-ARs on T cells controls the severity and fatality of acute GvHD after allo-HCT.

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Expression of β2-ARs on T cells controls the severity and fatality of ac...
(A) β2-AR expression in WT or β2-AR–/– CD4+ T cells harvested from spleen and liver on day 14 after allogenic T cell infusion. CD4+ T cells were gated from single live H-2b+H-2d–CD45+CD3+ cells, demonstrating an increase in β2-AR expression in the allo CD4+ T cells. All recipients received 3.5 × 106 WT C57BL/6 TCD-BM with or without T cells. (B) Body weight and survival of lethally irradiated BALB/c mice after allo-HCT BM alone or with 0.7 × 106 WT C57BL/6 or β2-AR–/– pan–T cells. (C) Body weight and survival of lethally irradiated C3H/SW mice after allo-HCT with BM alone or with 1.5 × 106 WT C57BL/6 or β2-AR–/– pan–T cells. (D) Body weight and survival of lethally irradiated BALB/c mice after allo-HCT with BM alone or with 0.2 × 106 WT C57BL/6 or β2-AR–/– CD4+ T cells. All experiments demonstrated increased GvHD severity and mortality in the absence of the β2-AR on T cells. Data pooled from 2 individual experiments, each with n = 6-8 per group to obtain total of n = 12–16 per group in B–D. For comparison of survival curves, a log-rank (Mantel-Cox) test was used in B–D. Two-way ANOVA with Tukey’s multiple comparisons test was used for body weight difference in B–D. *P < 0.05, **P < 0.01. Body weight and survival data are shown as means ± SEM. Other data are presented as median ± min to max.