doi: 10.1161/CIRCULATIONAHA.104.533463
(Circulation. 2005;112:1054-1062.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Blockade of Interleukin-12 Function by Protein Vaccination Attenuates Atherosclerosis
From the Division of Biopharmaceutics, Leiden University, Leiden, the Netherlands (A.D.H., P.d.V., T.J.C.v.B., J.K.); Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium (V.S.); Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université de Louvain, Louvain, Belgium (C.U.); and Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université de Louvain, Louvain, Belgium (J.C.R., J.v.S.).
Correspondence to A.D. Hauer, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, PO Box 9502, 2300 RA Leiden, The Netherlands. E-mail A.Hauer{at}LACDR.leidenuniv.nl
Received January 4, 2005; revision received May 4, 2005; accepted May 9, 2005.
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.
Methods and 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.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  K. L.L. Habets, G. H.M. van Puijvelde, L. M. van Duivenvoorde, E. J.A. van Wanrooij, P. de Vos, J.-W. Cohen Tervaert, T. J.C. van Berkel, R. E.M. Toes, and J. Kuiper Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice Cardiovasc Res, November 12, 2009; (2009) cvp338v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Carvalho, R. Pereira, and Y. Shoenfeld Vaccination, atherosclerosis and systemic lupus erythematosus Lupus, November 1, 2009; 18(13): 1209 - 1212. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Shen, E. Oesterling, A. Stromberg, M. Toborek, R. MacDonald, and B. Hennig Zinc Deficiency Induces Vascular Pro-Inflammatory Parameters Associated with NF-{kappa}B and PPAR Signaling J. Am. Coll. Nutr., October 1, 2008; 27(5): 577 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kleemann, S. Zadelaar, and T. Kooistra Cytokines and atherosclerosis: a comprehensive review of studies in mice Cardiovasc Res, August 1, 2008; 79(3): 360 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Wolfort, K. Y. Stokes, and D. N. Granger CD4+ T lymphocytes mediate hypercholesterolemia-induced endothelial dysfunction via a NAD(P)H oxidase-dependent mechanism Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2619 - H2626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.R.S. Girn, N.M. Orsi, and S. Homer-Vanniasinkam An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease Vascular Medicine, November 1, 2007; 12(4): 299 - 309. [Abstract] [PDF]
|
|
|
|
 |
|
 A. D. Hauer, G. H.M. van Puijvelde, N. Peterse, P. de Vos, V. van Weel, E. J.A. van Wanrooij, E. A.L. Biessen, P. H.A. Quax, A. G. Niethammer, R. A. Reisfeld, et al. Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 2050 - 2057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Gautier, T. Huby, B. Ouzilleau, C. Doucet, F. Saint-Charles, G. Gremy, M. J. Chapman, and P. Lesnik Enhanced Immune System Activation and Arterial Inflammation Accelerates Atherosclerosis in Lupus-Prone Mice Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1625 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M McMahon, J Grossman, W Chen, and B H Hahn Inflammation and the pathogenesis of atherosclerosis in systemic lupus erythematosus Lupus, November 1, 2006; 15(11_suppl): 59 - 69. [Abstract] [PDF]
|
|
|
|
 |
|
 G.H.M. van Puijvelde, A.D. Hauer, P. de Vos, R. van den Heuvel, M.J.C. van Herwijnen, R. van der Zee, W. van Eden, T.J.C. van Berkel, and J. Kuiper Induction of Oral Tolerance to Oxidized Low-Density Lipoprotein Ameliorates Atherosclerosis Circulation, October 31, 2006; 114(18): 1968 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wen, J. Gu, S.-L. Li, M. A. Reddy, R. Natarajan, and J. L. Nadler Elevated Glucose and Diabetes Promote Interleukin-12 Cytokine Gene Expression in Mouse Macrophages Endocrinology, May 1, 2006; 147(5): 2518 - 2525. [Abstract] [Full Text] [PDF]
|
|