In vitro effects of the CCR5 inhibitor maraviroc on human T cell function
In vitro effects of the CCR5 inhibitor maraviroc on human T cell function
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DOI：
10.1093/jac/dks432
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Plana, M.
中科院分区：
文献类型：
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作者：
Arberas, H.;Guardo, A. C.;Plana, M.
在使用CC趋化因子受体5 （CCR5）拮抗剂maraviroc治疗期间，除了其抗病毒作用外，还观察到几种潜在的免疫益处。我们的目的是分析体外CCR5阻断对T淋巴细胞功能和稳态的影响。将hiv阴性（n28）和处理过的hiv阳性（n27）个体的外周血单个核细胞（PBMCs）体外暴露于不同浓度（0.1100 M）的马拉韦洛克中。通过流式细胞术检测CD69、CD38、HLA-DR和CD25受体的表达以及CCR5的密度，分析其对T细胞活化的影响。自发和趋化因子诱导的趋化性通过transwell迁移试验来测量，多克隆诱导的增殖通过淋巴细胞增殖试验和羧基荧光素琥珀酰酰酯染色来评估。即使在低剂量（0.1 M）下，马拉韦洛克也能增加活化T细胞上CCR5表面的表达。在高浓度的马拉韦洛克中，激活标记物的频率和平均荧光强度略有差异。CD4和CD8 T淋巴细胞中CD25、CD38和HLA-DR的表达有降低的趋势，而CD69的表达有升高的趋势。马拉韦洛克明显抑制趋化因子诱导的T细胞迁移，且呈剂量依赖性。此外，在100 M时，马拉韦洛克有抑制T细胞增殖的趋势。这些数据表明，体外暴露于马拉韦洛克会降低T淋巴细胞上的一些激活表达标记物，并减少向趋化剂的迁移。这些结果支持CCR5阻断的额外免疫作用，并表明马拉韦洛克可能具有抑制hiv相关慢性炎症和激活的潜在能力，通过直接影响T细胞激活和减少淋巴结中淋巴细胞的滞留。
Several potential immunological benefits have been observed during treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc, in addition to its antiviral effect. Our objective was to analyse the in vitro effects of CCR5 blockade on T lymphocyte function and homeostasis.Peripheral blood mononuclear cells (PBMCs) from both HIV-negative (n28) and treated HIV-positive (n27) individuals were exposed in vitro to different concentrations of maraviroc (0.1100 M). Effects on T cell activation were analysed by measuring the expression of the CD69, CD38, HLA-DR and CD25 receptors as well as CCR5 density using flow cytometry. Spontaneous and chemokine-induced chemotaxis were measured by transwell migration assays, and polyclonal-induced proliferation was assessed by a lymphoproliferation assay and carboxyfluorescein succinimidyl ester staining.Maraviroc increases CCR5 surface expression on activated T cells, even at low doses (0.1 M). Slight differences were detected in the frequency and mean fluorescence intensity of activation markers at high concentrations of maraviroc. Expression of CD25, CD38 and HLA-DR tended to decrease in both CD4 and CD8 T lymphocytes, whereas expression of CD69 tended to increase. Maraviroc clearly inhibits T cell migration induced by chemokines in a dose-dependent manner. Moreover, at 100 M, maraviroc tends to inhibit T cell proliferation.These data showed that in vitro exposure to maraviroc decreases some activation expression markers on T lymphocytes and also migration towards chemoattractants. These results support the additional immunological effects of CCR5 blockade and suggest that maraviroc might have potential capacity to inhibit HIV-associated chronic inflammation and activation, both by directly affecting T cell activation and by reducing entrapment of lymphocytes in lymph nodes.