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The effects of β1 and β1+2 adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise.
Cell Stress and Chaperones ( IF 3.3 ) Pub Date : 2020-08-10 , DOI: 10.1007/s12192-020-01136-7
Hawley E Kunz 1, 2 , Nadia H Agha 1 , Maryam Hussain 3 , Emily C LaVoy 1 , Kyle A Smith 4 , Preteesh Mylabathula 4 , Douglass Diak 4 , Forrest L Baker 4 , Daniel P O'Connor 1 , Richard A Bond 5 , Emmanuel Katsanis 6 , Catherine M Bollard 7 , Richard J Simpson 1, 4, 6, 8
Affiliation  

The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β2 adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β1 + 2 AR antagonist (nadolol) or a β1 AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein–Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3+ T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β2 AR mediated, thus highlighting a role for the β2 AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β2 AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.



中文翻译:


β1 和 β1+2 肾上腺素能受体阻断对运动诱导的病毒特异性 T 细胞动员和离体扩增的影响:对细胞治疗和运动的抗病毒免疫作用的影响。



供体来源的病毒特异性 T 细胞 (VST) 的过继转移是同种异体造血细胞移植后感染的有效治疗方法。急性运动将效应淋巴细胞和 VST 动员到循环中,并增强 VST 的体外制造。本研究确定β2肾上腺素能受体 (AR) 信号传导是否会引发对急性运动的 VST 反应。健康参与者 ( n = 12) 在摄入安慰剂、β 1 + 2 AR 拮抗剂(纳多洛尔)或 β 1 AR 拮抗剂(比索洛尔)后完成 30 分钟的稳态自行车运动。运动前后计数巨细胞病毒(CMV)、EB病毒(EBV)和腺病毒(AdV)抗原的循环VST,并用病毒肽培养外周血单核细胞8天以扩增多VST。与安慰剂相比,纳多洛尔减弱了运动诱导的 CMV-VST 动员(安慰剂和纳多洛尔的Δ VST/100,000 CD3 + T 细胞 = 93 ± 104 分别为 22 ± 91; p = 0.036),而比索洛尔则没有。尽管这两种药物都会引起类似的运动心率和血压降低。仅在使用安慰剂进行运动后,循环 AdV 和 EBV VST(VST/mL 血液)才会增加。虽然不显着,但纳多洛尔部分减轻了运动引起的多 VST 扩展的增加,特别是在表现出运动引起的 VST 扩展增加的参与者中。 我们得出的结论是,运动引起的 VST 动员和扩张的增强至少部分是 β 2 AR 介导的,因此强调了 β 2 AR 在同种异体过继转移环境中增强 VST 免疫细胞治疗的靶向治疗中的作用。此外,长期定期运动可以通过频繁的 β 2 AR 依赖性动员和每次运动累积的 VST 重新分布,为宿主提供额外的病毒保护。

更新日期:2020-08-11
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