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PRECLINICAL STUDIES

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

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