Itani Hana A, McMaster William G, Saleh Mohamed A, Nazarewicz Rafal R, Mikolajczyk Tomasz P, Kaszuba Anna M, Konior Anna, Prejbisz Aleksander, Januszewicz Andrzej, Norlander Allison E, Chen Wei, Bonami Rachel H, Marshall Andrew F, Poffenberger Greg, Weyand Cornelia M, Madhur Meena S, Moore Daniel J, Harrison David G, Guzik Tomasz J
From the Division of Clinical Pharmacology, Department of Medicine (H.A.I., W.G.M., M.A.S., A.E.N., W.C., M.S.M., D.G.H.), General Surgery (W.G.M.), Division of Rheumatology, Department of Medicine (R.H.B.), Division of Endocrinology and Diabetes, Department of Pediatrics (A.F.M., D.J.M.), Division of Endocrinology, Department of Medicine (G.P.), Vanderbilt University Medical Center, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Divison of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CA (R.R.N., C.M.W.); Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland (T.P.M., A.M.K., A.K., T.J.G.); Department of Hypertension, Institute of Cardiology, Warsaw, Poland (A.M.K., A.P., A.J.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland (T.J.G.).
Hypertension. 2016 Jul;68(1):123-32. doi: 10.1161/HYPERTENSIONAHA.116.07237. Epub 2016 May 23.
Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-γ in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.
新出现的证据支持T细胞在高血压发生过程中起重要作用。由于这项工作主要是在实验动物中进行的，我们试图确定人类T细胞在高血压中是否被激活。我们使用了一种人源化小鼠模型，其中小鼠免疫系统被人类免疫系统所取代。与假手术处理的动物相比，血管紧张素II使收缩压升高至162 mmHg，而假手术组为116 mmHg。对胸段淋巴结、胸主动脉和肾脏进行流式细胞术分析发现，输注血管紧张素II后，人类白细胞（CD45(+)）和T淋巴细胞（CD3(+)和CD4(+)）的浸润增加。有趣的是，主动脉和淋巴结中的记忆T细胞（CD3(+)/CD45RO(+)）也有所增加。使用肼屈嗪和氢氯噻嗪预防高血压可防止T细胞在这些组织中积聚。对分离的人类T细胞和单核细胞的研究表明，血管紧张素II对T细胞产生细胞因子的能力或树突状细胞驱动T细胞增殖的能力没有直接影响。我们还观察到，与血压正常的人相比，高血压患者中产生白细胞介素-17A的循环CD4(+) T细胞以及产生干扰素-γ的CD4(+)和CD8(+) T细胞均增加。因此，在人源化小鼠模型中，人类T细胞会因高血压而被激活并侵入关键的终末器官组织。这种反应可能反映了体内遇到的高血压环境，而不是激素血管紧张素II的直接作用。
