(Circulation. 2001;104:197.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
In Vivo Downregulation of T Helper Cell 1 Immune Responses Reduces Atherogenesis in Apolipoprotein E-Knockout Mice
From INSERM U430, Hôpital Broussais (E.L., B.P., E.T., J.B., A.N.), and INSERM U460, Hôpital Bichat (G.C.), Paris, France; and the Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden (G.K.H.). The first 2 authors contributed equally to this work.
Correspondence to Antonino Nicoletti, PhD, INSERM U430, Hôpital Broussais, 96, rue Didot, Paris, France. E-mail antonino.nicoletti{at}brs.ap-hop-paris.fr
Background—— A chronic immune response involving proinflammatory T helper cell 1 (Th1) lymphocyte activation occurs in the atherosclerotic lesion, but whether this activation is protective or deleterious remains unclear.
Methods and Results—— We modulated the immune response of the atherosclerosis-prone apolipoprotein E-deficient (apoE-/-) mouse. Eight-week-old apoE-/- mice were treated daily with pentoxifylline (PTX), a known inhibitor of the Th1 differentiation pathway, or PBS (control) for 4 weeks or 12 weeks. Twelve-week PTX treatment reduced atherosclerotic lesion size by 60% (P<0.01). PTX-treated mice developed lesions that were limited to the degree of fatty streaks. In contrast, control mice developed mature fibrofatty atherosclerotic lesions. In parallel, the proportion of interferon (IFN)-
-producing Th1 splenic lymphocytes was significantly reduced by PTX, and lesion size was correlated to the proportion of IFN-+ T cells. In vitro addition of PTX to cultured spleen cells did not modify the production of IFN- but increased the production of IL-10 by T cells, indicating that PTX does not suppress IFN- production but rather blocks Th1 polarization while promoting Th2 polarization.
Conclusions—— Thus, PTX protected mice from atherosclerosis by reducing the Th1 polarization of T helper lymphocytes. This study demonstrates that the Th1 immune response associated with atherosclerosis is deleterious and that a modulation of the Th1 differentiation pathway may provide a new pharmacological tool to treat this disease.
Key Words: atherosclerosis • lymphocytes • inflammation • interleukins • inhibitors
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