Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis.
BACKGROUND
Interleukin-12 (IL-12) has been identified as a key inducer of a type 1 T-helper cell cytokine pattern, which is thought to contribute to the development of atherosclerosis. We sought to study the role of IL-12 in atherosclerosis by inhibition of IL-12 using a newly developed vaccination technique that fully blocks the action of IL-12.


RESULTS
LDL receptor-deficient (LDLr(-/-)) mice were vaccinated against IL-12 by 5 intramuscular injections of IL-12-PADRE complex in combination with adjuvant oil-in-water emulsion (low dose)/MPL/QS21 every 2 weeks. Two weeks thereafter, atherogenesis was initiated in the carotid artery by perivascular placement of silicone elastomer collars. IL-12 vaccination resulted in the induction of anti-IL-12 antibodies that functionally blocked the action of IL-12 as determined in an IL-12 bioassay. Blockade of IL-12 by vaccination of LDLr(-/-) mice resulted in significantly reduced (68.5%; P<0.01) atherogenesis compared with control mice without a change in serum cholesterol levels. IL-12 vaccination also resulted in a significant decrease in intima/media ratios (66.7%; P<0.01) and in the degree of stenosis (57.8%; P<0.01). On IL-12 vaccination, smooth muscle cell and collagen content in the neointima increased 2.8-fold (P<0.01) and 4.2-fold (P<0.01), respectively.


CONCLUSIONS
Functional blockade of endogenous IL-12 by vaccination resulted in a significant 68.5% reduction in atherogenesis in LDLr(-/-) mice. Vaccination against IL-12 also improved plaque stability, from which we conclude that the blockade of IL-12 by vaccination may be considered a promising new strategy in the treatment of atherosclerosis.
Hauer
A D
AD
Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands. A.Hauer@LACDR.leidenuniv.nl
Uyttenhove
C
C
de Vos
P
P
Stroobant
V
V
Renauld
J C
JC
van Berkel
T J C
TJ
van Snick
J
J
Kuiper
J
J
D000818:Animals; D001323:Autoantibodies / Q000627:therapeutic use; D001682:Biological Availability; D002340:Carotid Artery Diseases / Q000276:immunology* / Q000601:surgery; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000097:blood; D051379:Mice; D014612:Vaccines / Q000627:therapeutic use*
D001323:Autoantibodies; D000939:Epitopes; D014612:Vaccines; D018664:Interleukin-12; D007371:Interferon-gamma