title: In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice.
abstract: 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)-gamma-producing Th1 splenic lymphocytes was significantly reduced by PTX, and lesion size was correlated to the proportion of IFN-gamma(+) T cells. In vitro addition of PTX to cultured spleen cells did not modify the production of IFN-gamma but increased the production of IL-10 by T cells, indicating that PTX does not suppress IFN-gamma 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.
authors.affiliation: INSERM U430, Hôpital Broussais, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Laurat
authors.forename: B
authors.initials: B
authors.lastname: Poirier
authors.forename: E
authors.initials: E
authors.lastname: Tupin
authors.forename: G
authors.initials: G
authors.lastname: Caligiuri
authors.forename: G K
authors.initials: GK
authors.lastname: Hansson
authors.forename: J
authors.initials: J
authors.lastname: Bariéty
authors.forename: A
authors.initials: A
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000276:immunology*; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D010726:Phosphodiesterase Inhibitors; D014280:Triglycerides; D016753:Interleukin-10; D007371:Interferon-gamma; D010431:Pentoxifylline