Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000089083.61317.A1
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(Circulation. 2003;108:1232.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E–Knockout Mice
From the Institut National de la Santé et de la Recherche Médicale, INSERM U541, Institut Fédératif de Recherche Circulation Paris VII, Hôpital Lariboisière, Paris, France (Z.M., A.G., B.E., A.T.); INSERM U343 (H.G., N.F., F.C.); and TxCell, Bat. ARC (V.B.), Hôpital de l’Archet, Nice, France.
Correspondence to Ziad Mallat, MD, PhD, or Alain Tedgui, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la chapelle, 75010 Paris, France. E-mail mallat{at}larib.inserm.fr or tedgui@larib.inserm.fr
Received June 3, 2003; de novo received July 9, 2003; accepted July 21, 2003.
Background— 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.
Methods and Results— Clones of ovalbumin (OVA)–specific Tr1 cells expanded in vitro were administered intraperitoneally (106 cells per mouse) with their cognate antigen (50 µg 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-
(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.
Conclusions— Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.
Key Words: atherosclerosis • inflammation • immunity • lymphocytes • immunization
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