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(Circulation Research. 2006;99:E51.)
© 2006 American Heart Association, Inc.

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Maternal Immunization Programs Postnatal Immune Responses and Reduces Atherosclerosis in Offspring

Tomoya Yamashita, Stefan Freigang, Claudia Eberle, Jennifer Pattison, Sachin Gupta, Claudio Napoli, Wulf Palinski

From the Department of Medicine, University of California, San Diego. Present affiliations: Division of Cardiovascular and Respiratory Medicine (T.Y.), Kobe University School of Medicine, Kobe, Japan; Department of Immunology (S.F.), The Scripps Research Institute, La Jolla, Calif; and Department of General Pathology and Excellence Research Center on Cardiovascular Diseases (C.N.), 1st School of Medicine, Second University of Naples, Naples, Italy.

Correspondence to Wulf Palinski, Department of Medicine, 0682, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682. E-mail wpalinski{at}ucsd.edu

Maternal hypercholesterolemia during pregnancy increases offspring susceptibility to atherosclerosis by an oxidation-dependent mechanism. The present studies investigated whether maternal immunization with oxidized LDL (OxLDL) before pregnancy protects the fetus from atherogenic in utero programming by maternal hypercholesterolemia. Maternal immunization of NZW rabbits and LDL receptor–deficient mice indeed reduced atherosclerosis in adult offspring by up to 56%, but the protective effect could not be attributed to a reduction of fetal exposure to hypercholesterolemia alone, and even nonspecific immune stimulation with adjuvant only provided some protection. Unexpectedly, offspring of immunized mothers developed increased IgM antibodies to selective OxLDL epitopes and increased IgM-LDL immune complexes, compared with offspring of nonimmunized controls. Even naïve offspring of OxLDL-immunized mothers never exposed to postnatal hypercholesterolemia responded to a one-time OxLDL and KLH challenge with greater OxLDL-specific IgM responses, increased OxLDL-specific IgM-secreting B cells, and more IgM-LDL immune complexes. In contrast, maternal immunization with KLH, a T cell–dependent nonmammalian antigen, did not influence postnatal immune responses. Effects of maternal OxLDL-immunization on offspring B cells and selective antibodies were independent of transplacental passage of maternal immunoglobulins. Results show that maternal immunization with antigens prevalent in atherosclerotic lesions reduces atherogenesis in their offspring by mechanisms that include, but are not limited to, reduced fetal exposure to maternal hypercholesterolemia and lipid peroxidation. More importantly, they demonstrate in principle that maternal adaptive immunity to selective antigens influences postnatal B cell and antibody responses in offspring, and that modulation of in utero immune programming may influence immune-modulated diseases later in life.

Key Words: adaptive immunity • arteriosclerosis • immunization • in utero programming • oxidized LDL • developmental programming • prevention

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