title: Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype.
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 beta1 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 beta.
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Lutgens
authors.forename: K B
authors.initials: KB
authors.lastname: Cleutjens
authors.forename: S
authors.initials: S
authors.lastname: Heeneman
authors.forename: V E
authors.initials: VE
authors.lastname: Koteliansky
authors.forename: L C
authors.initials: LC
authors.lastname: Burkly
authors.forename: M J
authors.initials: MJ
authors.lastname: Daemen
mesh_terms: D000367:Age Factors; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand