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β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD
Hemn Mohammadpour, … , Elizabeth A. Repasky, Philip L. McCarthy
Hemn Mohammadpour, … , Elizabeth A. Repasky, Philip L. McCarthy
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(12):e137788. https://doi.org/10.1172/jci.insight.137788.
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Research Article Immunology Transplantation

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD

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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 3

The selective β2-AR agonist bambuterol ameliorates the severity and fatality of acute GvHD.

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The selective β2-AR agonist bambuterol ameliorates the severity and fata...
(A) Body weight, clinical score, and survival of lethally irradiated BALB/c mice after allo-HCT with 3.5 × 106 WT C57BL/6 TCD-BM alone or combined with 0.7 × 106 WT C57BL/6 pan–T cells treated with daily injections of saline and bambuterol. Data pooled from 2 individual experiments; n = 6–8 per group for a total of n = 12–16 per group. (B) Body weight, clinical score, and survival of lethally irradiated C3H/SW mice after allo-HCT with 3.5 × 106 WT C57BL/6 TCD-BM alone or combined with 1.5 × 106 WT C57BL/6 pan–T cells treated with daily injections of saline and bambuterol. Data pooled from 2 individual experiments; n = 4–7 per group for a total of n = 8–14 per group. Bambuterol significantly ameliorated aGvHD in the MHC and miHA mismatched models, as assessed by weight loss, clinical score, and survival. (C) T-bet+, Foxp-3+, IFN-γ+, IL-17+, and IL-10+ frequencies in CD4+ T cells within single live H-2b+H-2d–CD45+CD3+ cell populations from spleen and liver of mice 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 injections of saline and bambuterol at ST. Data pooled from 2 individual experiments; total n = 5–6 per group. There were significantly increased CD4+Foxp-3+ and CD4+IL-10+ and decreased CD4+T-bet+, CD4+IFN-γ+, and CD4+IL-17+ populations in the bambuterol-treated recipients. For comparison of survival curves, a log-rank (Mantel-Cox) test was used in A and B. For comparison of the means, an unpaired 2-tailed t test was used in C. Two-way ANOVA with Tukey’s multiple comparisons test was used for body weight and clinical score difference in A and B. *P < 0.05, **P < 0.01, ***P < 0.001. Body weight, clinical score, and survival data are shown as means ± SEM. Other data are presented as median ± min to max.

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