Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype

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 sta rted early (sge 5 wk) or was delayed until after the establishment of ather osclerosis (age 17 wk), In both the early and delayed treatment groups, ant i-CD40L antibody did not decrease plaque area or inhibit lesion initiation or age-related increase in lesion area. The morphology of initial lesions w as not affected, except for a decrease in T-lymphocyte content. Effects of anti-CD40L antibody treatment on the morphology of advanced lesions were pr onounced. In both the early and delayed treatment groups, T-lymphocyte cont ent was significantly decreased. Furthermore, a pronounced increase in coll agen content, vascular smooth muscle cell/myofibroblast content, and fibrou s cap thickness was observed. In the delayed treatment group, a decrease in lipid core and macrophage content occurred. Interestingly, advanced lesion s of anti-CD40L antibody-treated mice exhibited an increased transforming g rowth factor pi 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 li pid-poor collagen-rich stable plaque phenotype, Furthermore, delayed treatm ent 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 path ways and up-regulation of collagen-promoting factors like transforming grow th factor beta.