Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 4, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn025
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Vaccination against CD99 inhibits atherogenesis in LDL receptor-deficient mice
* Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, P.O. Box 9502, 2300 RA Leiden, The Netherlands
Max-Planck-Institute of Molecular Biomedicine, Röntgenstr. 20, D48149, Münster, Germany
# To whom correspondence should be addressed: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands; Tel: +31-(0)71-5274378; Fax: +31-(0)71-5276032; E-mail: j.kuiper{at}chem.leidenuniv.nl
Aims: Murine CD99 was recently found to be expressed on leukocytes and endothelial cells where it is concentrated at inter-endothelial contacts. Blockade of CD99 by specific antibodies inhibits leukocyte extravasation to inflamed sites in vivo. The aim of the present study is to show the role of CD99 in atherosclerosis using a CD99 vaccination protocol to block the function of CD99 during atherosclerosis.
Methods: We constructed a DNA vaccine against CD99 by cloning the extracellular domain of murine CD99 into pcDNA3. Vaccination was performed by oral administration of attenuated Salmonella typhimurium transformed with pcDNA3-CD99. This vaccination results in a CD99-specific, CD8-mediated cytotoxic response and subsequent reduction of CD99-expressing cells.
Results: We showed that CD99 is expressed on vascular endothelium overlying atherosclerotic plaques and found that CD99 expression is up-regulated during western-type diet feeding. CD99 vaccination induced the formation of CD8-positive T cells that were cytotoxic against cells transfected with pcDNA3-CD99. Activation of CD8+ T cells was demonstrated by a 30% increase in CD8+CD69+ double-positive T cells in spleen and mediastinal lymph nodes. Furthermore, lymphocytes isolated from CD99-vaccinated mice specifically lysed CD99-expressing cells. More importantly, vaccination against CD99 attenuated atherosclerotic lesion formation in the aortic valve leaflets by 38% and in the carotid artery by 69% as compared to mice that were vaccinated with a control vector. Furthermore, a lower number of cells were found in atherosclerotic lesions, implying that fewer leukocytes were recruited to these sites. These observations were accompanied by a decrease in CD99 expression on leukocytes.
Conclusion: We conclude that vaccination against CD99 decreases atherogenesis by the selective removal of CD99-expressing cells, which could reduce leukocyte recruitment into atherosclerotic lesions and attenuate atherogenesis.
KEYWORDS atherosclerosis; CD99; diapedesis; DNA vaccination
Time for primary review: 20
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