Atherosclerosis is an inflammatory condition. It is caused by dysfunction in the macrophage populations responsible for maintaining blood vessel walls, allowing fatty plaques to form, eventually leading to heart attack and stroke. This dysfunction is aggravated by a background of inflammatory signaling, and so there is some interest in finding ways to selectively interfere without preventing the beneficial activation of inflammation needed for normal immune function. That said, studies suggest that targeting inflammation in atherosclerosis is no more helpful than reductions in blood cholesterol, which is to say a modest reduction in mortality risk and only minimal reversal of existing lesions.
The protein CD40L is synthesized by, and expressed on the surface of specialized cells of the immune system. It is recognized by the CD40 protein, a membrane-bound receptor that is expressed on antigen-presenting cells. However, CD40L also binds to receptors on other cell types that have diverse physiological functions. Using a mouse model, researchers deleted the gene for CD40L specifically in T cells and platelets as well as its counterpart, CD40, on dendritic cells. They then crossed these mice with a strain that is particularly prone to develop atherosclerosis.
Secretion of interferon-gamma by T-cells is known to stimulate immune functions, but the CD40L-deficient T-cells were found to secrete less interferon-gamma than those in which the gene is intact. In addition, further experiments indeed showed that, in the absence of CD40L in T-cells, the atherosclerotic plaques that formed were smaller and more stable. This suggests that inhibition of CD40L could enhance the stability of atherosclerotic plaques, and thus reduce the incidence of heart attacks induced by the rupture of blood vessels.
Similar results were obtained in a mouse strain that was unable to produce CD40 in dendritic cells. Deletion of CD40L in platelets, on the other hand, had no effect on the incidence of atherosclerosis, but it was associated with a reduction in atherosclerosis-associated clot formation. Researchers are now extending their studies of the effects of CD40 und CD40L to other cell types, with the aim of developing drugs that can inhibit the functions of these proteins in a cell-specific fashion.