The cellular composition of human atherosclerotic plaques was analyzed by immunologic techniques. Plaques were removed from the internal carotid artery during surgery, and a panel of monoclonal antibodies was used to identify cell types.

To summarize, it is possible that T cell activation in the plaque has four different effects: a direct inhibition of smooth muscle proliferation mediated by IFN-gamma, an indirect stimulation of smooth muscle proliferation via IFN-induced macrophage activation, an induction of responsiveness to PDGF by induction of PDGF receptor expression, and finally, an up-regulation of HDL receptors. The net effect of T cell activation during the vascular response to injury may, therefore, depend on the balance between these mechanisms in any given situation during lesion development. T cell activation may itself be regulated by apolipoprotein E-containing LDL, which thus could form a direct link between lipoprotein accumulation and immune activation. We have recently tried to assess the effect of T cell activation during the response to experimental arterial injury with the use of a drug model. Cyclosporin A is a drug that specifically inhibits T cell activation. Rats treated with cyclosporin A for a short period had significantly smaller intimal lesions than did controls after balloon injury. This could be due to an inhibition of T cell activation, resulting in an inhibition of monocyte-macrophage activation and thereby loss of an important stimulus for intimal cell proliferation. When interpreting these results, one must, however, bear in mind that cyclosporin A could exert as yet unknown nonimmune vascular effects. It is also worth stressing that cell proliferation in the human atherosclerotic plaque may not be as high as in experimental animal lesions. In fact, cell replication may be a very rare event in the average advanced atherosclerotic plaque. Cell proliferation may, however, be associated with an episodic growth of lesions, and growth factor-mediated responses could, therefore, be important for the eventual clinical outcome in the individual patient. In conclusion, cytokines produced during the immune response affect growth and differentiation of vascular cells and could modulate both the response to injury and the local lipid metabolism in an atherosclerotic plaque There is indirect support for paracrine secretion of several of these factors in the atherosclerotic plaque, and activated T lymphocytes and macrophages are abundant in the plaque. This points to the possibility that specific immune responses are associated with the development of atherosclerosis. It is unknown, however, to what extent such immune responses occur or which antigens may elicit these responses.

A large proportion of the cells of the human atherosclerotic plaque is assumed to be derived from medial smooth muscle cells. In contrast to these, the cells of the plaque have the capacity to accumulate lipid, and they also proliferate at a higher rate than medial cells. It has therefore been suggested that smooth muscle cells undergo a change of phenotype during atherogenesis, but there has been no evidence for such a change on the molecular level. We have now analyzed carotid artery plaques using a battery of antibodies against cell surface and cytoskeletal antigens, and found that most of the cells express the class II transplantation antigen (Ia antigen) HLA-DR. Also, the beta chain of HLA-DR was detected by immunoblotting of plaque extracts with the OKIal nmonoclonal antibody. HLA-DR is normally present on cells of the immune system, but only 60% of the DR-positive cells of the plaque reacted with monoclonal antibodies specific for macrophages and lymphocytes. Many of the remaining DR-positive cells contained the muscle-specific intermediate filament protein, desmin. This indicates that smooth muscle cells of atherosclerotic plaques express DR antigen. In contrast, very few DRpositive cells were found in normal human arteries. This suggests that expression of class II antigen is part of a phenotypic change in smooth muscle cells in atherosclerosis.

A significant fraction of the arterial smooth muscle cells in atherosclerotic plaques and injury-induced intimal thickenings express class II major histocompatibility complex (Ia) antigens. This might be the consequence of gamma-interferon secretion by T lymphocytes also present in these lesions. We have therefore analyzed the effects of gamma-interferon on cultured rat aortic smooth muscle cells. Recombinant gamma-interferon inhibited smooth muscle proliferation in vitro in a dose-response relation; inhibition was detectable down to a concentration of 1 unit/ml. In similar concentrations, gamma-interferon also induced Ia expression by the cells. This suggested that Ia antigens might be selectively expressed by nonproliferating smooth muscle cells. In vivo, there was a strong negative correlation between Ia expression and 3H-thymidine labeling of smooth muscle cells in intimal thickenings induced by balloon catheter injury. In rats receiving continuous infusions of 3H-thymidine for two weeks after injury, Ia-positive 3H-positive cells had undergone fewer rounds of replication than Ia-negative ones. This indicates that Ia-expression both in vivo and in vitro is associated with a reduced proliferative capacity. These results suggest that gamma-interferon, a secretory product of activated T lymphocytes, acts as a natural regulator of smooth muscle cell growth and Ia expression in injury-induced intimal thickenings and atherosclerotic plaques.

Patients with CAD exhibited a cortisol pattern that markedly differed from controls. The data indicate that a dysfunctional HPA axis response involves a failure to contain inflammatory activity in CAD patients, thus providing a possible link between stress and inflammation in disease.