Lesion development and response to immunization reveal a complex role for CD4 in atherosclerosis

  • Zhou X
  • Robertson A
  • Rudling M
 et al. 
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Atherosclerosis is a complex disease, bearing many of the characteristics of a chronic inflammatory process. Both cellular and humoral immune responses may be involved in the disease development. Oxidized low-density lipoprotein (oxLDL) is suggested to be an autoantigen in atherosclerosis. A protective effect against atherosclerosis has been demonstrated in animals immunized with oxLDL. Such a protection is associated with elevation of T cell-dependent IgG antibodies against oxLDL. In addition, it has been shown that immunization with Freund adjuvant alone also confers protection against development of atherosclerosis. We therefore hypothesized that CD4+ T cells are critical in the development of atherosclerosis and that they are involved in protective immune reactions after immunization. The development of atherosclerosis was studied in apolipoprotein E knockout (apoE KO) mice and CD4/apoE double knockout (dKO) mice that were immunized with either oxLDL in Freund adjuvant or adjuvant alone, or left untreated. Our results show that (1) the absence of CD4+ cells in apoE KO mice leads to reduced atherosclerosis, indicating that CD4+ cells constitute a major proatherogenic cell population, and (2) the atheroprotective effect of LDL immunization does not depend on CD4+ cells, whereas (3) the atheroprotective effect of adjuvant injection is CD4-dependent. These findings demonstrate complex roles of immune cell-cell interactions in the regulation of the atherosclerotic process and point to several possible targets in the treatment and prevention of atherosclerosis.

Author-supplied keywords

  • *Immunization
  • Animals
  • Antigen-Presenting Cells/immunology/metabolism
  • Antigens, CD/biosynthesis/genetics
  • Antigens, CD4/genetics/immunology/*physiology
  • Antigens, Differentiation, Myelomonocytic/biosynth
  • Aortic Diseases/blood/etiology/*immunology/patholo
  • Apolipoproteins E/deficiency/genetics
  • Arteriosclerosis/blood/etiology/*immunology/pathol
  • Autoantibodies/biosynthesis/blood/immunology
  • Autoantigens/*immunology
  • CD4-Positive T-Lymphocytes/*immunology
  • Cholesterol/blood
  • Disease Progression
  • Female
  • Freund's Adjuvant/pharmacology/therapeutic use
  • Genes, MHC Class II
  • Histocompatibility Antigens Class II/biosynthesis
  • Immunoglobulin G/biosynthesis/blood/immunology
  • Interferon-gamma/biosynthesis
  • Interleukin-4/biosynthesis/genetics
  • Lipoproteins, LDL/*immunology/therapeutic use
  • Malondialdehyde/*analogs & derivatives/immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger/biosynthesis/genetics
  • Random Allocation
  • Receptors, Immunologic/metabolism
  • Receptors, Scavenger
  • T-Cell Antigen Receptor Specificity
  • Triglycerides/blood
  • Vascular Cell Adhesion Molecule-1/biosynthesis/gen
  • Vasculitis/blood/complications/immunology/preventi

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  • X Zhou

  • A K Robertson

  • M Rudling

  • P Parini

  • G K Hansson

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