Mallat Ziad, Gojova Andrea, Brun Valérie, Esposito Bruno, Fournier Nathalie, Cottrez Françoise, Tedgui Alain, Groux Hervé
Institut National de la Santé et de la Recherche Médicale, INSERM U541, Institut Fédératif de Recherche Circulation Paris VII, Hôpital Lariboisière, Paris, France.
Circulation. 2003 Sep 9;108(10):1232-7. doi: 10.1161/01.CIR.0000089083.61317.A1. Epub 2003 Aug 11.
T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.
Clones of ovalbumin (OVA)-specific Tr1 cells expanded in vitro were administered intraperitoneally (106 cells per mouse) with their cognate antigen (50 microg of OVA subcutaneously in complete Freund's adjuvant [CFA]) to female apolipoprotein E-knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (P<0.0001), a decrease in the production of interferon-gamma (P<0.001), and an increase in interleukin-10 production (P<0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A-stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls (P=0.002 to P<0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice.
Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.
1型辅助性T细胞（Th1）反应在动脉粥样硬化中起促进作用。我们推测，一种名为1型调节性T细胞（Tr1）的新型T淋巴细胞亚型的过继转移将通过诱导旁观者免疫抑制来抑制Th1反应，从而限制动脉粥样硬化的发展。
将体外扩增的卵清蛋白（OVA）特异性Tr1细胞克隆腹腔注射（每只小鼠106个细胞），同时注射其同源抗原（50μg OVA皮下注射于完全弗氏佐剂[CFA]中）给雌性载脂蛋白E基因敲除小鼠。一组小鼠仅接受（OVA/CFA）免疫，不注射Tr1细胞。另外两个对照组不进行免疫，分别注射Tr1细胞或生理盐水。治疗9周后，注射（OVA/CFA）+OVA特异性Tr1细胞的小鼠Th1反应显著降低，表现为OVA特异性IgG2a血清水平降低（P<0.0001）、干扰素-γ产生减少（P<0.001）以及培养的脾脏和淋巴T细胞产生的白细胞介素-10增加（P<0.001），与对照组相比。此外，伴刀豆球蛋白A刺激的脾脏细胞产生的细胞因子显示，接受（OVA/CFA）+Tr1治疗的小鼠明显转向调节性免疫反应。这与接受（OVA/CFA）+Tr1治疗的小鼠胸主动脉和主动脉窦的动脉粥样硬化病变大小与对照组相比显著减小有关（P=0.002至P<0.0001）。注射（OVA/CFA）+Tr1的小鼠斑块中巨噬细胞和T细胞的积聚明显低于对照小鼠的斑块。
Tr1型调节性免疫反应可减少实验性动脉粥样硬化的发展。
