This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2006.11.054v1 50/6/540    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (31) Citing Articles via Google Scholar Google Scholar Articles by Caligiuri, G. Articles by Nicoletti, A. Search for Related Content PubMed PubMed Citation Articles by Caligiuri, G. Articles by Nicoletti, A. Related Collections Related Articles

PRECLINICAL STUDY

Phosphorylcholine-Targeting Immunization Reduces Atherosclerosis

Giuseppina Caligiuri, MD, PhD^_*,_*, Jamila Khallou-Laschet, PhD^_*, Marta Vandaele, MSc^_*, Anh-Thu Gaston, BSc^_*, Sandrine Delignat, BSc^_*, Chantal Mandet, BSc, Heinz V. Kohler, MD, PhD, Srini V. Kaveri, DVM, PhD^_* and Antonino Nicoletti, PhD^_*

^_* Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Paris, France
Centre de Recherche des Cordeliers, Université René Descartes Paris 5, Paris, France
Immpheron, Lexington, Kentucky.

Manuscript received October 11, 2005; revised manuscript received October 6, 2006, accepted November 16, 2006.

^_* Reprint requests and correspondence: Dr. Giuseppina Caligiuri, INSERM UMR S 872, équipe 16, Centre de Recherche des Cordeliers, 15, rue de l’Ecole de Médecine, Paris, F-75006, France. (Email: giuseppina.caligiuri{at}umrs681.jussieu.fr).

Objectives: The present study evaluated the effect of phosphorylcholine (PC) immunization on the extent of experimental atherosclerosis.

Background: Immunization against oxidized lipoprotein (oxLDL) or Streptococcus pneumoconiae reduces atherosclerosis. Phosphorylcholine is the main epitope recognized by both antipneumococcus and anti-oxLDL antibodies. Therefore we reasoned that PC-specific antibodies might play an important role in atherogenesis.

Methods: Apolipoprotein E knockout mice were immunized with PC every second week over 4 months. At the end of the study, serum antibodies directed to either PC or oxLDL were measured. Splenic and peritoneal B cells were analyzed by flow cytometry. Aortic root atherosclerotic lesions were quantified by morphometry and phenotyped by immunohistochemistry. Immune and control sera were also tested for their effect on foam cell formation in macrophage culture in the presence of oxLDL.

Results: The PC-immunized mice showed 3-fold increase in titers of anti-PC and -oxLDL antibodies compared with control mice (p < 0.01). The PC-immunized mice also showed a significant increase in the number of splenic mature B cells. The extent of atherosclerotic aorta root lesions was reduced by >40% in the PC-immunized mice (p < 0.01). Immunohistochemistry showed reduced expression of major histocompatibility complex class II antigens (p < 0.05) and the presence of B-cell clusters in plaques of PC-immunized mice. Finally, PC-immune serum was able to reduce macrophage-derived foam cell formation in the presence of oxLDL in vitro.

Conclusions: Phosphorylcholine immunization drives a specific humoral immune response that reduces foam cell formation in vitro and is atheroprotective in vivo.

Abbreviations and Acronyms   ApoE = apolipoprotein E   KLH = keyhole limpet hemocyanin   KO = knockout   oxLDL = oxidized low-density lipoprotein   PBS = phosphate-buffered saline   PC = phosphorylcholine   TC = total cholesterol

Related Articles

Inside This Issue of JACC
J. Am. Coll. Cardiol. 2007 50: A35-A36. [Full Text] [PDF]

This article has been cited by other articles:

				S. V. Kaveri, G. J. Silverman, and J. Bayry Natural IgM in Immune Equilibrium and Harnessing Their Therapeutic Potential J. Immunol., February 1, 2012; 188(3): 939 - 945. [Abstract] [Full Text] [PDF]

				A. C. Doran, M. J. Lipinski, S. N. Oldham, J. C. Garmey, K. A. Campbell, M. D. Skaflen, A. Cutchins, D. J. Lee, D. K. Glover, K. A. Kelly, et al. B-Cell Aortic Homing and Atheroprotection Depend on Id3 Circ. Res., January 6, 2012; 110(1): e1 - e12. [Abstract] [Full Text] [PDF]

				S. Tsimikas, A. Miyanohara, K. Hartvigsen, E. Merki, P. X. Shaw, M.-Y. Chou, J. Pattison, M. Torzewski, J. Sollors, T. Friedmann, et al. Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression. J. Am. Coll. Cardiol., October 11, 2011; 58(16): 1715 - 1727. [Abstract] [Full Text] [PDF]

				A. Ravandi, S. M. Boekholdt, Z. Mallat, P. J. Talmud, J. J. P. Kastelein, N. J. Wareham, E. R. Miller, J. Benessiano, A. Tedgui, J. L. Witztum, et al. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study J. Lipid Res., October 1, 2011; 52(10): 1829 - 1836. [Abstract] [Full Text] [PDF]

				S. Ajeganova, C. Ehrnfelt, R. Alizadeh, M. Rohani, T. Jogestrand, I. Hafstrom, and J. Frostegard Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset--a prospective cohort study Rheumatology, October 1, 2011; 50(10): 1785 - 1793. [Abstract] [Full Text] [PDF]

				Y. I. Miller, S.-H. Choi, P. Wiesner, L. Fang, R. Harkewicz, K. Hartvigsen, A. Boullier, A. Gonen, C. J. Diehl, X. Que, et al. Oxidation-Specific Epitopes Are Danger-Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate Immunity Circ. Res., January 21, 2011; 108(2): 235 - 248. [Abstract] [Full Text] [PDF]

				G. D. Wool, V. G. Cabana, J. Lukens, P. X. Shaw, C. J. Binder, J. L. Witztum, C. A. Reardon, and G. S. Getz 4F Peptide reduces nascent atherosclerosis and induces natural antibody production in apolipoprotein E-null mice FASEB J, January 1, 2011; 25(1): 290 - 300. [Abstract] [Full Text] [PDF]

				M. Sampi, M. Veneskoski, O. Ukkola, Y. A. Kesaniemi, and S. Horkko High Plasma Immunoglobulin (Ig) A and Low IgG Antibody Titers to Oxidized Low-Density Lipoprotein Are Associated with Markers of Glucose Metabolism J. Clin. Endocrinol. Metab., May 1, 2010; 95(5): 2467 - 2475. [Abstract] [Full Text] [PDF]

				R. Fiskesund, B. Stegmayr, G. Hallmans, M. Vikstrom, L. Weinehall, U. de Faire, and J. Frostegard Low Levels of Antibodies Against Phosphorylcholine Predict Development of Stroke in a Population-Based Study From Northern Sweden Stroke, April 1, 2010; 41(4): 607 - 612. [Abstract] [Full Text] [PDF]

				K. L.L. Habets, G. H.M. van Puijvelde, L. M. van Duivenvoorde, E. J.A. van Wanrooij, P. de Vos, J.-W. C. 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, February 1, 2010; 85(3): 622 - 630. [Abstract] [Full Text] [PDF]

				J. J. Carrero, X. Hua, P. Stenvinkel, A. R. Qureshi, O. Heimburger, P. Barany, B. Lindholm, and J. Frostegard Low levels of IgM antibodies against phosphorylcholine-A increase mortality risk in patients undergoing haemodialysis Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3454 - 3460. [Abstract] [Full Text] [PDF]

				M. J. Lewis, T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard Immunoglobulin M Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, August 4, 2009; 120(5): 417 - 426. [Abstract] [Full Text] [PDF]

				K. R. Sipido, A. Tedgui, S. D. Kristensen, G. Pasterkamp, H. Schunkert, M. Wehling, P. G. Steg, W. Eisert, F. Rademakers, B. Casadei, et al. Identifying needs and opportunities for advancing translational research in cardiovascular disease Cardiovasc Res, August 1, 2009; 83(3): 425 - 435. [Full Text] [PDF]

				H. Gronlund, G. Hallmans, J. H. Jansson, K. Boman, M. Wikstrom, U. de Faire, and J. Frostegard Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden European Journal of Cardiovascular Prevention & Rehabilitation, June 1, 2009; 16(3): 382 - 386. [Abstract] [Full Text] [PDF]

				K. Hartvigsen, M.-Y. Chou, L. F. Hansen, P. X. Shaw, S. Tsimikas, C. J. Binder, and J. L. Witztum The role of innate immunity in atherogenesis J. Lipid Res., April 1, 2009; 50(Supplement): S388 - S393. [Abstract] [Full Text] [PDF]

				C. J. Binder, K. Hartvigsen, and J. L. Witztum Promise of Immune Modulation to Inhibit Atherogenesis J. Am. Coll. Cardiol., August 7, 2007; 50(6): 547 - 550. [Full Text] [PDF]