Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype
- Esther Lutgens*,†,
- Kitty B. J. M. Cleutjens*,
- Sylvia Heeneman*,
- Victor E. Koteliansky‡,
- Linda C. Burkly‡, and
- Mat J. A. P. Daemen*,§
- Departments of *Pathology and †Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands; and ‡Biogen Incorporated, 12 Cambridge Center, Cambridge, MA 02142
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Edited by Henry Metzger, National Institutes of Health, Bethesda, MD, and approved March 21, 2000 (received for review December 29, 1999)
Abstract
In the present study, we investigated the role of the CD40L-CD40 pathway in a model of progressive atherosclerosis. ApoE−/− mice were treated with an anti-CD40L antibody or a control antibody for 12 wk. Antibody treatment started early (age 5 wk) or was delayed until after the establishment of atherosclerosis (age 17 wk). In both the early and delayed treatment groups, anti-CD40L antibody did not decrease plaque area or inhibit lesion initiation or age-related increase in lesion area. The morphology of initial lesions was not affected, except for a decrease in T-lymphocyte content. Effects of anti-CD40L antibody treatment on the morphology of advanced lesions were pronounced. In both the early and delayed treatment groups, T-lymphocyte content was significantly decreased. Furthermore, a pronounced increase in collagen content, vascular smooth muscle cell/myofibroblast content, and fibrous cap thickness was observed. In the delayed treatment group, a decrease in lipid core and macrophage content occurred. Interestingly, advanced lesions of anti-CD40L antibody-treated mice exhibited an increased transforming growth factor β1 immunoreactivity, especially in macrophages. In conclusion, both early and delayed treatment with an anti-CD40L antibody do not affect atherosclerotic lesion initiation but do result in the development of a lipid-poor collagen-rich stable plaque phenotype. Furthermore, delayed treatment with anti-CD40L antibody can transform the lesion profile from a lipid-rich to a lipid-poor collagen-rich phenotype. Postulated mechanisms of this effect on plaque phenotype are the down-regulation of proinflammatory pathways and up-regulation of collagen-promoting factors like transforming growth factor β.
Footnotes
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↵ § To whom reprint requests should be addressed. E-mail: MDA{at}LPAT.AZM.NL.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 6930.
- Abbreviations:
- TGF,
- transforming growth factor;
- ASMA,
- α-smooth muscle actin;
- VSMC,
- vascular smooth muscle cell
- Copyright © 2000, The National Academy of Sciences
