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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have established the presence of high numbers of activated T lymphocytes and "aberrant" expression of major histocompatibility complex class II antigens by endothelial and smooth muscle cells in human atherosclerotic lesions, implicating the involvement of a local cellular immune response. The identity of the antigen(s) eliciting this immune response, the extent of their effect, and the atherogenic stage at which they occur remain to be determined. In the present studies, 120 normocholesterolemic New Zealand White rabbits were immunized one or more times with various antigens, with or without adjuvants. The antigens and adjuvants included human or rabbit atherosclerotic lesion proteins, ovalbumin, Freund's complete and/or incomplete adjuvants, recombinant mycobacterial heat shock protein 65 (hsp65), and two hsp-free adjuvants, Ribi complete adjuvant and lipopeptide. In addition, some groups received a high-cholesterol diet. Sixteen weeks after the first immunization the animals were killed, and arteriosclerotic lesions in the intima of the aortic arch were found to have developed only in those animals immunized with antigenic preparations containing hsp, either in the form of whole mycobacteria or as purified recombinant hsp65, although their serum cholesterol levels were normal. No arteriosclerotic changes exceeding those of controls were found in the other groups, irrespective of the antigen used. Immunohistopathologic examination revealed that the lesions contained 20% T cells, 10-30% macrophages, and 10-40% smooth muscle cells. Analysis of the peripheral blood T-lymphocyte proliferative responses revealed that the occurrence of lesions was positively correlated with the presence of hsp65-reactive T cells, suggesting that hsp65 is involved in the induction of arteriosclerotic lesions. Furthermore, combined immunization with hsp-containing material and a cholesterol-rich diet provoked development of significantly more severe atherosclerosis and the appearance of characteristic foam cells. We conclude that an (auto)immune response to hsp may initiate the development of atherosclerosis and that a high blood cholesterol level is only one albeit a very important risk factor.
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PMID:Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. 161 4

Human atherosclerotic plaques contain significant numbers of T lymphocytes and monocyte-derived macrophages. Cytokines released from activated T lymphocytes induce aberrant expression of major histocompatibility complex class II (Ia) antigens by vascular smooth muscle cells and may also regulate cell proliferation and metabolism in the vessel wall. We have analyzed the arteries of cholesterol-fed rabbits to study the sequence of lymphocyte and monocyte entry into the forming atherosclerotic lesion. Rabbits were fed 0.3% cholesterol for 1-10 weeks, and monoclonal antibodies to rabbit leukocyte differentiation antigens and Ia antigen were applied to sections of the aorta. Monocytes were already observed 1 week after initiation of cholesterol feeding, and they accumulated in the intima, where they formed the bulk of the foam cell-rich lesion. T lymphocytes also adhered to the aortic surface from 1 week onward, and also accumulated in the lesion, although in lower proportions than did monocytes. In 10-week lesions, approximately 6% of cells expressed the T-lymphocyte marker L11/135. Ia antigen expression was frequent throughout the lesion in all phases of its development, and most of the Ia-expressing cells could be identified as monocyte-derived macrophages. These data indicate that the cholesterol-fed rabbit is a useful model for studying the role of monocytes and T lymphocytes in atherosclerosis.
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PMID:Immunohistochemical detection of macrophages and T lymphocytes in atherosclerotic lesions of cholesterol-fed rabbits. 202 9

There is evidence that fatty streaks in arteries can transform into atherosclerotic plaques. Mononuclear cells, including both monocytes and lymphocytes, are among the first cells participating in the development of atherosclerosis of experimental animals. To investigate the roles of different cell types in human atherosclerosis, we enumerated and compared the cellular compositions of normal intima, the transition zone (the area between the normal intima and the core of fatty streaks), fatty streaks, and plaques in young (age 16-30 years) and aged (over 60 years) human specimens using double-staining immunofluorescence with a series of monoclonal and polyclonal antibodies. T lymphocytes, both T helper/inducer (70% of T cells) and T suppressor/cytotoxic (30%) phenotypes, were found in every stage of atherosclerosis, constituting 30 to 40% of total cells in fatty streaks and transition zones of young subjects, and occasionally even in normal intima. Seventy percent of these T cells were HLA-DR positive, which indicated that most of them were activated. Macrophages were most frequent in fatty streaks and around the necrotic core of plaques. Smooth muscle cells, increasing from 5 to 30% with lesion progression, were HLA-DR positive where activated T helper cells occurred in the vicinity. The intracellular presence of the invariant gamma chain confirmed that HLA-DR was actually synthesized by these smooth muscle cells. Endothelial cells were HLA-DR positive above those regions of the lesions where HLA-DR-positive cells had accumulated, but not in normal intima, again suggesting induction of HLA-DR expression by T-cell-derived gamma-interferon. Furthermore, most HLA-DR-positive cells were also identified as HLA-DP and HLA-DQ positive. This aberrant major histocompatibility complex class II antigen expression in smooth muscle and endothelial cells may participate in the perpetuation of the atherogenetic autoimmune reaction.
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PMID:Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. 220 32

Hypercholesterolemia is a major risk factor for development of atherosclerosis. In experimental animals fed a high-cholesterol diet, monocytes adhere to the arterial endothelium and penetrate into the intima where they differentiate into macrophages and ingest lipids thus giving rise to fatty streaks, the earliest type of atherosclerotic plaque. Macrophages express few receptors for normal low density lipoprotein (LDL) but can take up oxidized LDL by way of a scavenger receptor. The present study was designed to investigate the possible role of oxidized LDL in recruitment of resident intimal macrophages. We found that oxidized LDL induced enhanced expression of major histocompatibility complex class II molecules on human monocytes and U937 cells, a well-established system for studies of monocytic differentiation. Oxidized LDL also induced enhanced expression of the surface antigen LeuM3 but caused decreased expression of CD4 antigen, a pattern compatible with expression of a more-differentiated macrophage-like phenotype. Oxidized LDL also initiated aggregation of monocytes and U937 cells and stimulated adhesion of U937 cells to cultured endothelial cells. The results indicate that oxidized LDL may contribute to development of atherosclerosis by inducing adhesion of monocytes to the arterial intima and by stimulating intimal monocytes to differentiate into resident macrophages.
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PMID:Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. 230 May 83

An association between cytomegalovirus infection, cardiac allograft rejection, and atherosclerosis has been described. It has been suggested that cytomegalovirus induces major histocompatibility complex antigen expression in the graft and may trigger rejection. The induction of major histocompatibility complex antigens is thought to be mediated by interferon-gamma produced by activated T cells during the infection. To study whether cytomegalovirus infection induces major histocompatibility complex class II antigen expression in heart endothelium, cultured rat heart endothelial cells were infected with rat cytomegalovirus. The infection was shown by cytopathic effect and immunofluorescence using monoclonal cytomegalovirus-specific antibodies. Major histocompatibility complex class II antigen expression was analyzed before and during cytomegalovirus infection by two different methods, by a fluorescence-activated cell sorter and immunoperoxidase techniques using monoclonal antibodies. Uninfected endothelial cell cultures were treated with interferon-gamma and used as positive controls of class II induction. Induction of class II antigens was recorded in cytomegalovirus-infected endothelial cell cultures, and during the course of infection the class II expression increased toward the appearance of cytopathic effect. In uninfected cells, class II was induced by interferon-gamma, but this induction could be inhibited by adding antiinterferon-gamma antibody to the cultures. However, anti-interferon-gamma did not inhibit the induction of class II caused by cytomegalovirus. In conclusion, cytomegalovirus induced major histocompatibility complex class II antigen expression in rat heart endothelial cells in vitro. This induction of class II was independent of interferon-gamma and was caused by the virus itself. Direct induction of class II antigens by cytomegalovirus in heart endothelium may also be involved in rejection mechanisms in vivo.
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PMID:Cytomegalovirus induces class II expression in rat heart endothelial cells. 803 20

It has been suggested that immune responses are involved in the development of atherosclerosis. We have evaluated this possibility by analyzing immunocompetent cells in a murine model of the disease. Apolipoprotein E knockout (apoE -/-) mice are genetically hypercholesterolemic due to targeted disruption of the apolipoprotein E gene and develop severe atherosclerosis. Such mice were fed either standard pellets or a diet containing 1.25% cholesterol. Lesions were analyzed from mice at 9 and 16 weeks of age. Immunohistochemical staining of fatty streaks showed that CD4+ T cells were frequent, both in clusters and as single cells. In advanced atherosclerotic plaques, CD4+ T cells were prominent in the fibrous cap and subendotbelially, whereas CD8+ T cells were sparse. The CD25 subunit of the interleukin-2 receptor, which is a marker for activated T cells, was expressed in CD4-rich areas and the major histocompatibility complex class II antigen, I-A(b), which is induced by cytokines released from activated T cells, was also found in the lesions. These data indicate that CD4+ T cells participate in the formation of atherosclerotic lesions in genetically hypercholesterolemic apoE -/- mice. They suggest that immune activation is part of the disease process, and we speculate that a direct link may exist between cholesterol accumulation and T cell activation, possibly by autoimmune responses to modified lipoproteins.
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PMID:Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. 870 75

Immunocytochemical analyses of human plaques and experimental arterial lesions have implicated activated lymphocytes and monocytes in the pathogenesis of atherosclerosis, as demonstrated by the expression of interleukin-2 (IL-2) membrane receptors and major histocompatibility complex class II epitopes. The objective is to determine if targeting these cells with an IL-2 receptor-specific chimeric toxin, DAB486-IL-2, can inhibit experimental post-angioplasty vascular neointimal thickening. Twenty-two atherogenically modeled rabbits were treated in vivo with DAB486-IL-2 (0.1 mg/kg per day i.v.; n = 11) or placebo (n = 11) for 10 days following aortic balloon angioplasty (4 atm x 30 s each x 2 dilatations). In vitro 3H-leucine incorporation studies of mononuclear leukocyte and vascular smooth muscle cell protein synthesis inhibition by DAB486-IL-2 were also performed. Angioplasty sites were examined for evidence of hyperproliferative atherosclerotic narrowing by quantitative angiography and histomorphometry of neointimal cross-sectional area at baseline and 6 weeks after injury. In vitro Concanavalin-A stimulated rabbit mononuclear leukocyte protein synthesis was 50% inhibited by DAB486-IL-2 at a concentration (IC50) of 6 x 10(-11) M. Rabbit vascular smooth muscle cells were approximately 150-fold less sensitive to DAB486-IL-2 (IC50 = 10(-8) M). In vivo studies showed no change in angioplasty site angiographic minimum luminal diameter at 6 weeks in DAB486-IL-2 treated animals (from 2.96 +/- 0.52 to 2.96 +/- 0.48 mm; percent cross-sectional area reduction = 1 +/- 10%; P = N.S.). In control animals, luminal diameter decreased from 2.79 +/- 0.4 to 2.32 +/- 0.52 mm at 6 weeks, and percent cross-sectional area was reduced by 34 +/- 14% (P < 0.01 vs. placebo). Quantitative histomorphometric angioplasty segmental intimal cross-sectional area reduction of treated and placebo vessels also differed significantly (19 +/- 16% vs. 31 +/- 21%; P < 0.05). DAB486-IL-2 caused no adverse effects on animal survival, weight or hepatic transaminase levels. We conclude that post-angioplasty administration of the chimeric toxin DAB486-IL-2 inhibits angiographic narrowing and neointimal thickening in the atherogenic rabbit model. Although this IL-2 receptor-specific molecule was cytotoxic in vitro for activated mononuclear leukocytes and vascular smooth muscle cells, systemic toxicity did not occur in vivo at a dose comparable to that evaluated in clinical trials of this agent. Potential anti-proliferative effects of this chimeric toxin may be mediated by direct local inhibition of leukocyte-mediated inflammation, or through the indirect modification of vascular cell mitogenesis and cytokine release.
Atherosclerosis 1996 Sep 27
PMID:Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis. 887 29

Platelet activating factor (PAF) is a phospholipid with proinflammatory and thrombogenic properties, which has been implicated in inflammatory disorders including vasculitis and asthma. PAF-like compounds are present in oxidized LDL (oxLDL), which has been detected in the atherosclerotic lesion, where it may activate monocytes, macrophages, and T cells. OxLDL may therefore both initiate and perpetuate inflammatory reactions in the artery wall. Herein we demonstrate that PAF has the capacity to induce enhanced interferon gamma (IFN-gamma) secretion in peripheral blood mononuclear leukocytes (PBMCs), as does oxLDL. Both oxLDL- and PAF-induced IFN-gamma secretions were inhibited by a specific PAF-receptor antagonist, WEB 2170. PAF-like lipids in oxLDL could thus be responsible for oxLDL-induced activation of immune-competent cells. The effects of PAF and oxLDL were inhibited by antibodies to major histocompatibility complex class II and thus depend on accessory cells like monocytes. Both PAF and oxLDL induced tumor necrosis factor-alpha (TNF-alpha) synthesis in peripheral blood. PAF-mediated TNF-alpha production was inhibited by WEB 2170, whereas oxLDL-induced TNF-alpha was only partially inhibited. These findings indicate that both PAF and oxLDL have the capacity to induce TNF-alpha, which may increase atherogenesis due to its pleiotropic proinflammatory effects. Our findings suggest that the PAF receptor plays an important role in the inflammatory component of atherosclerosis.
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PMID:Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism. 915 62

Peroxisome proliferator-activated receptors (PPARs) are essential in glucose and lipid metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as diabetes and dyslipidemia. Conversely, antidiabetic glitazones and hypolipidemic fibrate drugs, known as PPARgamma and PPARalpha ligands, respectively, reduce the process of atherosclerotic lesion formation, which involves chronic immunoinflammatory processes. Major histocompatibility complex class II (MHC-II) molecules, expressed on the surface of specialized cells, are directly involved in the activation of T lymphocytes and in the control of the immune response. Interestingly, expression of MHC-II has recently been observed in atherosclerotic plaques, and it can be induced by the proinflammatory cytokine interferon-gamma (IFN-gamma) in vascular cells. To explore a possible role for PPAR ligands in the regulation of the immune response, we investigated whether PPAR activation affects MHC-II expression in atheroma-associated cells. In the present study, we demonstrate that PPARgamma but not PPARalpha ligands act as inhibitors of IFN-gamma-induced MHC-II expression and thus as repressors of MHC-II-mediated T-cell activation. All different types of PPARgamma ligands tested inhibit MHC-II. This effect of PPARgamma ligands is due to a specific inhibition of promoter IV of CIITA and does not concern constitutive expression of MHC-II. Thus, the beneficial effects of antidiabetic PPARgamma activators on atherosclerotic plaque development may be partly explained by their repression of MHC-II expression and subsequent inhibition of T-lymphocyte activation.
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PMID:PPARgamma but not PPARalpha ligands are potent repressors of major histocompatibility complex class II induction in atheroma-associated cells. 1186 26

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.
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PMID:PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. 1193 39


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