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Review Immune Mechanisms in Atherosclerosis Goran K. Hansson, Lena Jonasson, Paul S. Seifert, and Sten Stemme T Monocytes and Macrophages Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 he atherosclerotic plaque bears many similarities to chronic inflammatory conditions, perhaps the most striking one being the accumulation of macrophages in both situations. This has been pointed out repeatedly over the years, and Rudolf Virchow1 described atherosclerosis as a chronic irritation of the vessel wall. Poole and Florey,2 in their classic papers on the effects of mechanical injury to the aorta, pointed out the involvement of leukocytes in the response to injury process. A few years later, Roberts3 found that serum sickness significantly aggravates cholesterol-induced atherosclerosis. Minick and Murphy4 subsequently elucidated the role of immune complexes, and it is clear today that circulating immune complexes are potent pro-atherogenic factors in experimental animal models. One of the major functions of macrophages is to participate in the immune response by presenting foreign antigen to T lymphocytes. The macrophage internalizes foreign antigens by endocytosis, partially degrades them in its lysosomes, and then transfers antigen fragments, to the cell surface. The fragments associate with polymorphic cell-surface MHC proteins, and the antigen receptor of the T lymphocyte binds to this macromolecular complex on the macrophage surface.1011 Studies involving cholesterol-fed animals in the latter part of the 1970s re-emphasized the importance of monocytes in atherosclerosis. Fowler et al. 12 demonstrated that many foam cells in the lesions of cholesterol-fed rabbits express Fc and C3b receptors characteristic for monocytes and macrophages. A provocative series of electron micrographic studies on monocytes in early lesions of fat-fed swine by Gerrity and his colleagues1314 showed that monocytes enter very early lesions and pre-atherosclerotic areas, penetrate the endothelium, and take up cholesterol in the intjma Other monocytes, now filled with lipid, seemed to emigrate from the forming lesion. Similar electron microscopic findings were reported by Faggiotto et al. 1 5 1 6 The hypothesis was formulated that monocytes mobilize cholesterol from the lipid-laden intima and therefore constitute an important defense mechanism in cholesterol-induced atherosclerosis.12-15 The relevance of immune mechanisms to human atherosclerosis has been less clear. It has been difficult to assess the contribution of immunocompetent cells to plaque, and very few studies have examined the prevalence of immune responses to microorganisms or specific major histocompatibilrty complex (MHC) alleles in atherosclerotic patients. Progress in the field of immunology during recent years has, however, made it possible to characterize the inflammatory cell populations that form the atherosclerotic plaque and to evaluate the effects of immune cytokines on the cells of the vasculature. Our own work showed that monocytes preferentially bind to injured endothelium.1718 This is at least in part due to an interaction between the Fc receptor of the monocyte and IgG that has been absorbed onto cytoskeletal intermediate filaments.1920-21 The binding of IgG to the cytoskeleton also activates the complement cascade.21-22 This, in turn, generates the anaphylatoxin C5a, which is an important chemoattractant for monocytes and granulocytes.21 A hypothetical scheme for the relationship between endothelial injury and monocyte recruitment is shown in Figure 1. Another potentially significant mechanism for recruitment of monocytes to the vessel wall is via endothelial expression of specific leukocyte adhesive proteins (see below). Immune Components In Human Plaques The three major cellular components of the human atherosclerotic plaque are the smooth muscle cell, which dominates the fibrous cap; the macrophage, which is the most abundant cell type in the lipid-rich core region; and the lymphocyte, which is mainly found in the fibrous cap. 6 - 8 Whereas smooth muscle cells and macrophages were identified by light and electron microscopy several years ago, 86 the degree of lymphocytic infiltration was not apparent until monoclonal antibodies were used for immunohistochemical analysis of the plaque. 78 From the Department of Clinical Chemistry, Gothenburg University, Gothenburg, Sweden. This work was supported by grants from the Swedish Medical Research Council (project 6816) and the Swedish National Association against Heart and Chest Diseases. Paul S. Serfert was the recipient of a Fogarty International Postdoctoral Research Fellowship. Address for correspondence: Dr. G6ran Hansson, Department of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital, S-413 45 Gothenburg, Sweden. Received December 27,1988; revision accepted May 3,1989. (Arteriosclerosis 9:567-578, September/October 1989) The role of monocytes in human atherosclerosis has been more difficult to determine. Early electron microscopic studies had suggested that macrophages derived from monocytes are present in the human lesion. 2324 - 28 It was, however, evident from all light microscopic, cytochemical, and uttrastructural analyses of human plaques that many of the cells could not be identified as either smooth muscle cells or monocytes. Monoclonal antibody technology has made it possible to address the question of cellular composition of the 567 568 ARTERIOSCLEROSIS VOL 9, No 5, SEPTEMBER/OCTOBER 1989 Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 Figure 1. Postulated mechanism of complement activation and leukocyte recruitment in endothellal cell injury. When the plasma membrane is damaged (A), macromolecules of the extracellular fluid enter the cytosol. These macromolecules include IgG and complement factor, Ckj, which may bind to high-affinity binding sites on cytoskeletal intermediate filaments and mitochondria (B). The formation of like IgG-CI complexes on intracellular structures (C) activates the complement cascade, leading to opsonization of these structures by complement components (C3b) as well as to release of chemotactic anaphylatoxlns (C5a). Chemotactically recruited monocytes and granulocytes may then phagocytize and eliminate the remnants of the injured cell (D). (Reprinted from Hansson et al. 21 with kind permission of Experimental Cell Research and Academic Press, Incorporated.) plaque with sensitive and specific reagents. Monocytes share a set of specific cell-surface proteins that do not appear on other cells. Some of the first markers that were supposedly monocyte specific, like the Fc receptor and the MHC class II proteins, have turned out to be more broadly distributed. 2627 Other monoclonal antibodies, however, appear to react exclusively with monocyte-specific surface proteins. Such leukocyte differentiation antigens have recently been evaluated in a series of international workshops, and antigenic clusters of differentiation have been identified. For identification of monocytes and macrophages, the most widely used antibodies are those that recognize the CD14 antigen cluster. (CD numbers of antigens refer to clusters of differentiation defined by the International Workshops on Leukocyte Differentiation Antigens.28) This family of antibodies includes AntiLeu-M3, My4, Mo2, and others. Another monocytespecific antibody is HAM35.8 The identification of monocytes in atherosclerotic plaques by monoclonal antibody cytochemistry was made simultaneously by Vedeler et al., 29 Aqel et al., 30 and ourselves.31 We performed a detailed quantitative analysis of cell types in complicated human plaques7 and found that 60% of the cells in the lipid core express the CD14 antigen (Figure 2). In the fibrous cap, on the other hand, smooth muscle cells dominate, and only 20% of the cells were identified as monocyte derived by immunocytochemistry. Subsequent studies of plaques have confirmed that monocyte-derived macrophages are present both in the early fibrofatty lesion and in the complicated plaque. 73233 Immunohistochemical analyses of the human fatty streak lesion 3438 showed that it is dominated by monocytederived macrophages. The evolution of the fatty streak to the advanced lesion has been controversial, but recent studies of hypercholesterolemic rabbits and monkeys1519'36 show that at least some fatty streaks are converted into fibrous plaques during the progression of the disease. T Lymphocytes In Atherosclerosis The close functional relationship between macrophages and T lymphocytes suggested to us that T cells could be present in the atherosclerotic plaque. In fact, lymphocytes had been observed in human plaques and experimental lesions in several microscopic studies,23-242837-38-39 but their quantitative significance or functional state could not be estimated. We included the CD3 antibody, which recognizes all T lymphocytes, as well as the subtype markers CD4 and CD8, in our panel for immunocytochemical analysis of carotid plaques. Substantial amounts of CD3-positive T lymphocytes could be detected in the plaque with these reagents (Figure 2). Approximately one fifth of the cells in the fibrous cap were T cells.7 In contrast, almost no B or natural killer (NK) cells were found. Other immunohistochemical studies have shown that lymphocytes are present in fatty streaks, fibrous plaques, and advanced plaques.8-33-35-40 IMMUNE MECHANISMS IN ATHEROSCLEROSIS At 60% 7 9% Hansson et al. 569 M 2*% T rty. Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 Rgure 2. Monocyte-derlved macrophages (M) and T lymphocytes (T) in the carotid atherosclerotic plaque. Values are expressed as percentages of total cells in different regions of the plaque and are based on Immunohlstochemlcal analyses of endarterectomy samples (data from reference 7). CD4-type T lymphocytes induce antibody production and regulate cell-mediated immune responses. They were found to quantitatively dominate in all regions of the complicated carotid plaque,7 as they do in peripheral blood. In contrast, CD8 cells are more frequent in early plaques40 and also in the fatty streak,35 and they dominate over CD4 cells in the intimal thickening surrounding the complicated plaque.7 The CD8 subtype contains most of the cytoxic T cell activity. One possibility is that CD8 cells are involved in the initiation of the lesion, but that a switch toward a CD4-dominated situation occurs during progression of the individual lesion. The finding of T lymphocytes in the plaque does not necessarily imply that these cells are immunologically active. It is possible that they could represent a dormant population of blood cells trapped during plaque formation. This can be clarified by immunocytochemical analyses, since activated T lymphocytes express cell-surface proteins that are absent from resting T cells. Approximately one third of the T lymphocytes in the plaque were found to express the activation markers, HLA-DR and VLA-1 (very late activation antigen-1), with fewer T cells expressing the receptor for interieukin-2.41 This pattern is similar to that observed in the synovium of patients with rheumatoid arthritis.42 It has been suggested that a phenotype with a high VLA-1 frequency and a low interieukin-2 receptor frequency represents a long-standing form of T cell activation.43 It is, however, unknown what role T lymphocytes play in atherosclerosis. Do they, for example, represent an immune response to a specific component of the plaque? This issue needs to be clarified and requires an immunologic characterization of T lymphocytes derived from plaque tissue. Aberrant Class IIMHC Antigen Expression T lymphocytes are not activated by foreign antigens in solution but by peptide fragments of antigens bound to MHC proteins on the cell surface of antigen-presenting cells. 1011 The class I family of MHC proteins comprises HLA-A, -B, and -C; participates in the activation of CD8type T lymphocytes; and is expressed on most cell types. 1011 MHC class II proteins, in contrast, are normally expressed mainly by cells of the immune system. 1011 They include HLA-DR, -DQ, and -DP antigens and are restriction elements in the activation of CD4 type T lymphocytes.10'11 The limited tissue distribution of class II antigens may be important in the control of the immune response, since CD4 cells have important "helper" functions in the induction of immune responses. Although normally restricted to cells of the immune system, class II MHC antigens are expressed by parenchymal and stromal cells in many inflammatory and autoimmune conditions. For instance, class II antigens appear on synovial cells in rheumatoid arthritis,44 on thyrocytes in Graves' disease,45 and on enterocytes in celiac disease.48 They can also be induced during infections, for example, in the urinary tract47 and gut.48 In experimental immune responses, injection of a foreign antigen results in the appearance of antigen-presenting, class II M H C expressing cells together with T cells. 48 - 67 These findings suggest that "aberrantly" class ll-expressing cells can play a central role in the immune response of autoimmune diseases. 570 ARTERIOSCLEROSIS V O L 9, No 5, SEPTEMBER/OCTOBER 1989 Capillary endothelial cells appear to express class II MHC antigens constitutively,9809 whereas large-vessel endothelium is normally class ll-negative. Pober and Gimbrone60 have shown that cultured endothelial cells express the class II antigen, HLA-DR, when treated with interferon-y (IFN-y). Such HLA-DR-positive endothelial cells can serve as antigen-presenting cells and thus substitute for macrophages during the initiation of the immune response.61 It appears likely that endothelial antigen presentation, for example, in the microvasculature, may be physiologically and pathophysiologically important for the initiation and propagation of local immune responses. Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 Vascular smooth muscle cells do not normally express class II antigens but may do so in atherosclerosis.26-27 In fact, the majority of all plaque cells express HLA-DR. Many of these are macrophages, but approximately one third of the smooth muscle cells express HLA-DR and -DQ.27 Vascular HLA-DR expression is also observed in vasculitides. Moyer and Reinish62 have shown that smooth muscle cells can express class II antigens in the autoimmune MRL/lpr mouse during vasculitis. This appears to result in an attack by specific T lymphocytes recognizing smooth muscle autoantigens. Similarly, in vitro immunization of lymphocytes with smooth muscle cells results in vasculitis when these lymphocytes are injected into a recipient.83 HLA-DR expression is also frequent in giant cell arteritis of the human temporal artery in humans.64 In this case, however, expression is restricted to the macrophages present in the arterrtic lesion. The observations of class II expressing smooth muscle cells and macrophages in the vicinity of T lymphocytes suggested that a lymphokine induced the expression of class II antigens. This was supported by the observation that the addition of recombinant IFN-y to cultured rat aortic smooth muscle cells induces class II antigen expression. 6668 Both HLA-DR and HLA-DQ were further enhanced by treatment with tumor necrosis factor, emphasizing the importance of lymphocyte-macrophage interactions (S. Stemme, unpubl. obs.). It is now of central importance to find out whether class II expression by smooth muscle cells has a functional significance. At present, data are conflicting. Murine microvascular smooth muscle cells can present ovalbumin to ovalbumin-specific T cell clones in an MHCrestricted manner.87 In contrast, human vascular smooth muscle cells did not induce proliferation of allogeneic T lymphocytes.68 The discrepancy could be due to species differences; alternatively, smooth muscle cells may be able to present foreign antigens to T cell lines and partially activated T cells, but not to native T cells. Humoral Components of the Immune System Localization of Immunoglobullns and Complement Atherosclerotic plaques contain deposits of immunoglobulins that are not found in nonatherosclerotic arterial tissue.6970 Similar deposits are found in the lesions of cholesterol-fed rabbits and consist of IgG associated with collagen fibrils, cytoskeletal filaments, and cell surfaces of mononuclear cells. 7172 It is not known whether any of this IgG represents specific antibodies to arterial components. It is, however, interesting that complement factors are found with a similar tissue distribution, 697073 suggesting that tissue-deposited IgG may induce a local complement activation in the plaque. Support for this hypothesis was recently obtained by demonstration of the C5b-9 complex in atherosclerotic plaques.7475 This macromolecular complex is formed as the end product of the complement cascade and serves as a device for perforating cell membranes. The assembly of the C5b-9 complex from the C5b, C6, C7, C8, and C9 proteins creates conformational neoantigens that are not present on any of the native components.78 Antibodies to the neoantigens are specific for the C5b-9 macromolecular complex, and the presence of C5b-9 complexes in a tissue, therefore, indicates that complement activation has taken place. The finding of C5b-9 on fibrillar structures in the fibrous cap and in an amorphous pattern in the lipid core strongly suggests that complement activation is occurring in the plaque. Recent studies of cholesterol-fed rabbits show that local complement activation occurs at a very early stage of cholesterol deposition in arterial tissue, before any fatty streak-like lesions are observed.77 This supports the idea that cholesterol deposits can activate complement and that products released during activation serve as chemotactic stimuli for monocytes to enter the forming lesion.77 Further support for the hypothesis that complement activation may play an important role in atherosclerosis was obtained by recent studies of C3-binding proteins in plaques.78 It was observed that the smooth muscle cells of atherosclerotic plaques (but not of normal arteries) express decay-accelerating factor, which protects the cells from complement-mediated lysis by inhibiting C3/C5 convertase formation. This shows that the phenotypic changes of smooth muscle cells during atherogenesis involve the induction of complement regulatory molecules. A more thorough review of complement activation in atherosclerosis has recently been published.79 Circulating Autoantlbodles and Immune Complexes Serum sickness has been repeatedly correlated with development or aggravation of the atherosclerotic process.3 Minick and Murphy4 showed that injection of foreign serum proteins synergize with a cholesterol-rich diet to produce rapidly developing atherosclerotic lesions. This may be initiated by immune complex-mediated complement activation, resulting in endothelial injury and followed by the deposition of immune complexes and complement activation in deeper layers of the arterial wall. 80 The work of Cerilli et al. 81 shows that autoimmune responses to endothelial antigens correlate strongly to peripheral vascular disease and suggests that antiendothelial autoantibodies are involved in the pathogenesis of atherosclerosis (see Table 1). Clarkson and Alexander82 proposed that vasectomy may lead to accelerated atherosclerosis due to the presence of circulating immune complexes consisting of sperm proteins and autoantibodies. Subsequent studies, how- IMMUNE MECHANISMS IN ATHEROSCLEROSIS Table 1. Antigens Proposed or Shown to Elicit Arrtibody Responses Related to Atherosclerosis Antigen Clinical condition Endothelial surface antigen Reference Table 2. Hansson et al. Cytoklnes of Immune System Cytokine Cellular source lnterleukln-1 Monocyte-macrophage Endothelial cell Smooth muscle cell Other cell types T lymphocytes 81 Sperm components Vasectomy 82,83 lnterleukln-2 Herpes viruses Viral infections 84,85,86 lnterieukln-3 lnterieukin-4 lnterleukin-5 lnterleukin-6/ interferon-02 Interferon-a Interferon-y Tumor necrosis factor (TNF-a) Lymphotoxin LJpoproteins Qlycosylated lipoprotelns Cardiotipin Oxidized lipid Structural vessel wall antigens Milk proteins Diabetes 88-92 93,94 96 97-100 Malignant hypertension 101, 102 103, 104 Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 ever, have not confirmed any proatherogenic effect of vasectomy.83 Several microorganisms, particularly herpes viruses, have been implicated in the pathogenesis of atherosclerosis. 848586 Trie local response to such pathogens is likely to involve both cell-mediated and antibody-based immune reactions. Autoantibodies to an endogenous virus can induce complement-mediated lysis of vascular smooth muscle cells leading to arteritis in SL/Ni mice.87 The relevance of these findings to human atherosclerosis is, however, still unclear. Autoantibodies to lipoproteins have been observed in patients with atherosclerosis.88-82 The frequency of such autoantibodies in the population at large is, however, still unclear. Lipoproteins that are extracellularty modified may be recognized as neoantigens by the immune system. One example is glycosylated low density lipoproteins (LDL), which give rise to autoantibodies in patients with diabetes93 and in cholesterol-fed rabbits. Such autoantibodies form immune complexes with glycosylated LDL, and these complexes are rapidly cleared from the circulation via macrophage Fc receptors.94 Delivery of LDL as part of immune complexes could, therefore, serve as a mechanism for cholesterol accumulation in macrophage-derived foam cells.95 The lipid components of the plaque may elicit immune responses as well as the proteins, and antibodies to phospholipids have been observed in sera from patients with myocardial infarction and other atherosclerotic diseases. It has, therefore, been suggested that patients with cardiolipin antibodies are at risk for recurrent cardiovascular disease.96 PeriadventitJal infiltrates consisting of T and B lymphocytes and plasma cells are frequent around atherosclerotic plaques,97-100 and may perhaps represent a specific immune response to plaque components such as oxidized lipid.97 Antibodies, as well as T cell responses to antigens present in extracts of the arterial wall, have been described both in atherosclerosis101 and in malignant hypertension.102 571 (TNF-0) Platelet-derived growth factor T lymphocytes T lymphocytes T lymphocytes Many cell types Leukocytes T lymphocytes Monocyte-macrophage Smooth muscle cell T lymphocytes Monocyte-macrophage Endothelial cell Smooth muscle cell Megakaryocyte/platelet It has been suggested that they aggravate vascular damage. In conclusion, it seems clear that autoantibodies to lipoproteins, lipids, or other components of the arterial wall can be formed during the course of an atherosclerotic disease. The development of an antibody response to arterial structural proteins may be analogous, for example, to the formation of antibodies to thyroglobulin in thyroiditis. Molecules released after tissue damage could be presented to T lymphocytes by local antigenpresenting cells. A delicately balanced immunologic tolerance to this autoantigen breaks down, and the immune system responds by antibody production.49 Currently available data suggest that several types of autoantibodies can form in atherosclerosis. It is not clear, however, whether they appear frequently enough to be useful as markers of disease or of a specific state of the disease. We know even less about the pathogenetic significance of such autoantibodies in atherosclerosis. Interleukln Secretion The activation and propagation of the immune response depends not only on interactions between cell surface molecules, but also on humoral factors. In fact, the cells of the immune system can be viewed as endocrine cells, which, in their activated state, produce high amounts of hormone-like substances called interieukins or cytokines (Table 2). Several of these molecules have been shown to affect growth and gene expression in vascular cells, and, although the interieukin-vessel wall field merits a review of its own, we will briefly describe some aspects of interieukinvascular interactions. lnterleukln-1 and Growth Stimulation Monocytes and macrophages, when activated, produce several factors that are important for immune and inflammatory responses. They also secrete growth-promoting 572 ARTERIOSCLEROSIS VOL 9, No 5, SEPTEMBER/OCTOBER 1989 Table 3. Vascular Effects of lrrterleukin-1 Cells Endothelial cells Induces reorganization of endothelial monolayers Induces procoagulant activity Stimulates adhesion of granulocytes, monocytes, and lymphocytes by inducing expression of specific adhesive proteins Induces IL-1 release by positive feedback Stimulates proliferation Increases vascular permeability Smooth muscle cells Induces IL-1 release by positive feedback Stimulates proliferation Table 4. Vascular Effects of Tumor Necrosis Factor Reference 106 107 108,109 110 Cells Endothelial cells Induces reorganization of monolayers Induces procoagulant activity Stimulates leukocyte adhesion by inducing expression of adhesive surface proteins Inhibits proliferation in vitro Induces angiogenesis Superinduces MHC gene expression Reference 124 107 125,126 128 128 129,130 Smooth muscle cells 111 Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 112 Superinduces class I MHC genes Modulates IFN-y-induced class II MHC genes 113 MHC=major histocompatbillty complex, IFN-y=interferon-y. 114 that TNF-a can be produced by vascular smooth muscle cells. 130 TNF-a induces vascular and inflammatory responses similar to those of IL-1 (Table 4), but may, in addition, cause tumor cytotoxicity and the cachexia seen in malignant diseases. 117119 ' 132133 TNF, therefore, interferes with metabolic processes at many steps. One of them is the control of lipotytic activity. Upoprotein lipase (LPL) is synthesized by parenchymal cells of several tissues including skeletal and cardiac muscle, adipose tissue, and also the arterial wall. 1 3 4 1 3 5 1 3 6 TNF and also IL-1 suppress LPL activity in adipocytes, and this may be an important part of the catabolic activity of these cytokines. 132137138139 LPL is secreted by macrophages in culture, and it has been proposed that macrophages induce local lipolysis in the atherosclerotic plaque by LPL secretion. 140141 We have recently found that immunoreactive LPL cannot be detected in macrophages of atherosclerotic lesions.142 Instead, the smooth muscle cell is the major source of immunodetectable LPL in both the atherosclerotic and the normal artery.142 HLA-DR-expressing muscle cells are, however, frequently LPL-negative. This may imply that inflammatory stimuli such as IFN-yand TNF-a may inhibit local LPL production in the plaque. Induces synthesis of growth-inhibitory prostaglandlns 114 Induces PDGF secretion 115 PDGF=platelet-dertved growth factor, IL-1=interieukin-1. substances, the best-known of which is platelet-derived growth factor.108 lnterleukin-1 (IL-1) is probably the best characterized monocyte-derived irrterleukin (Table 3). It was originally identified as a lymphocyte-activating factor in conditioned media from activated monocytes.116-119 It has subsequently been purified, cloned, and characterized. There are two forms of IL-1, a and 0, with similar effects including induction of tissue catabolism and acute inflammatory responses.116-119 When added to cultured endothelia) cells, IL-1 induces a variety of responses, resulting in expression of adhesive surface proteins, metabolic changes, and structural reorganization (Table 3).106-109,120,121 /\ common denominator for these responses may be an induction of a pro-inflammatory endothelial phenotype. LJbby and co-workers122 have shown that IL-1 may participate in autocrine and paracrine growth regulation in the vessel wall. They first observed that endothelial cells produce IL-1 when stimulated, for example, by endotoxin. They then found that smooth muscle cells, when appropriately stimulated, also synthesize and secrete large amounts of IL-1. 1 2 3 IL-1 production by both endothelial and smooth muscle cells is stimulated in the presence of IL-1, forming a positive-feedback loop. 110113 It has recently been shown 115 that IL-1 induces secretion of plateletderived growth factor (PDGF) by smooth muscle cells, and this may account for the growth-promoting effect of IL-1. However, IL-1 also induces production of growthinhibitory prostaglandins,114 and the in vivo effect of a local IL-1 release in the arterial wall is therefore unclear. Tumor Necrosis Factor-a and Upolysls The activated macrophage produces a 17-kD protein called tumor necrosis factor (TNF). It is also known as cachectin, and since the lymphocyte makes a structurally related substance, lymphotoxin, the macrophage product is often identified as TNF-a. It has recently been shown 131 131 Interferon-y and Growth Control The resting T lymphocyte does not secrete any hormonelike substances, but the activated cell is a rich source of biologically active proteins. The best studied of these is IFN-y. (See Table 5.) IFN-ywas initially recognized as an antiviral factor, but it has subsequently become clear that it is a major activating factor of the immune system. 148147 IFN-y has three major effects: it induces expression of MHC genes, inhibits cell proliferation, and induces antiviral activity. In addition, it affects expression of a variety of genes in many different cell types including macrophages and vascular cells.148 Poberetal.80'81 demonstrated that IFN-y induces expression of class II genes of the MHC by a variety of target cells including endothelial cells. Such class ll-expressing endothelial cells become capable of presenting antigens IMMUNE MECHANISMS IN ATHEROSCLEROSIS Table 5. Vascular Effects of Interferon-y Cells Endothelial cells Induces reorganization of monolayers Inhibits proliferation Superinduces class 1 MHC genes Induces class II MHC genes Induces "new" surface proteins associated with autoimmune response (Kawasaki disease) Increases vascular permeability Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 Inhibits PDGF and IL-1 expression Smooth muscle cells Inhibits proliferation Superinduces class I MHC genes Induces class II MHC genes Reference 124 143 144 60,61 145 112 158 66,131 131 65,66 MHC=major histocompatibility complex, PDGF=plateletderfved growth factor, IL-1 =interleukin 1. to T cells, thus substituting for macrophages in the initiation of the immune response. A number of other genes are also regulated by IFN-y. Among these are the collagens, the synthesis of which are inhibited on the RNA level by IFN-y. 148160 IFN-y may also reduce the elastin content of connective tissues by increasing elastase activity.151 IFN-y is a very potent growth inhibitor. As little as 10 U/ml of IFN-y, corresponding to approximately 2 ng/ml, significantly inhibits the proliferation of rat aortic smooth muscle cells.86 Similar observations have been made on human arterial smooth muscle cells131 and on human endothelial cells.143 Since IFN-y induces expression of class II antigens on vascular and other cell types, the expression of such antigens by cells that do not normally express these proteins may be looked upon as markers of IFN-y effects on the cells. We applied this reasoning in a response-to-injury model of atherosclerosis. A proliferative intimal lesion was produced in rat carotid arteries by balloon catheterization. This was stained for the rat class II antigen, I-A, and analyzed for cell proliferation by 3 Hthymidine autoradiography.88 Smooth muscle cells that expressed I-A did not proliferate, indicating that IFN-y secreted by T cells present in the lesion acts as a paracrine growth inhibitor during the arterial response to injury.66 It has recently been shown that IFN-y up-regulates high density lipoprotein (HDL) receptors on cultured fibroblasts.152 It appears likely that this effect is secondary to the growth-inhibitory effect of IFN-y, which would lead to a reduced demand for cholesterol.162 Another interferon-like protein, interferon-/32 (IFN-02), may serve as an autocrine growth regulator. Its expression is induced by other cytokines such as TNF and PDGF, and IFN-02 effectively inhibits cell proliferation. 1531 " IFN-02 is Hansson et al. 573 identical to IL-6, and has also been called hybridoma growth factor and B cell differentiation factor. Monoklnes, Lymphoklnes, and Regulation of Vascular Cell Growth and Differentiation A multitude of different growth-promoting and growthinhibiting factors may be made by the inflammatory cells present in the atherosclerotic plaque. What may be the net effect of this? Our studies on the effects of IFN-y in the vessel w a l l 2 6 2 7 6 6 6 6 1 3 1 show that: 1) IFN-y is locally released by activated T lymphocytes in the atherosclerotic plaque and during the response to injury in experimental models, 2) IFN-y induces class II MHC antigen expression in neighboring smooth muscle cells and macrophages by paracrine stimulation, and 3) IFN-y probably functions as a growth inhibitor in the plaque, since IFN-ystimulated, class ll-expressing smooth muscle cells do not proliferate. (See Figure 3.) IFN-y and other T cell products are, however, activators of macrophages,146147 and this may lead to other effects. The activated macrophage secretes IL-1 and PDGF, which are growth promoters for smooth muscle cells, 114115 and also TNF-a, which has important metabolic effects.132 Endothelial cells also produce growth factors such as PDGF, 155 ' 156157 which may promote growth of smooth muscle cells. It has recently been shown that IFN-y inhibits endothelial expression of PDGF and IL-1, demonstrating another level for T cell regulation of vascular growth.158 Induction of cell proliferation depends not only on the presence of growth factors, but also on the responsiveness of the cells to these growth factors. Although smooth muscle cells and fibroblasts in culture express receptors for PDGF and respond vividly to the addition of PDGF to the culture medium, 188186 recent immunohistochemicaJ studies show that PDGF (B type) receptors are not normally expressed on vascular cells in situ. 168 Thus, the normal arterial media is largely devoid of such receptors. Receptors are, however, expressed on smooth muscle cells of the atherosclerotic intima and also on intimal smooth muscle cells in inflammatory diseases such as rheumatoid arthritis and transplant rejection.199 A common denominator for all these conditions, including atherosclerosis, is that macrophages and T lymphocytes infiltrate the intima, and we have, therefore, proposed that inflammatory cell interactions lead to release of an unknown factor that induces PDGF receptors on intimal smooth muscle cells. This, in turn, would lead to induction of cell proliferation in a PDGF-rich environment.159 Summary 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-y, 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 574 ARTERIOSCLEROSIS VOL 9, No 5, SEPTEMBER/OCTOBER 1989 P tffereniwitiorv Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 6KH88 Figure 3. Possible cell-cell Interactions between vascular and Inflammatory cells In the atherosclerotic plaque. Cytokines known to exert effects on vascular cells are included, and synthesizing as well as target cells are Indicated. Tumor necrosis factor (TNF) produced by macrophages (M<£) may affect endothelial organization and regulate endothelial expression of adhesive proteins and T cell function, expression of major histocompatibillty complex (MHC) genes, and perhaps aiso lipolytic activity in smooth muscle cells (SMC), lnterteukin-1 (IL-1) may also affect endothelial morphology and expression of adhesive proteins. It is a co-factor for T cell growth, and may promote growth of SMC. IL-1 could induce secretion of platelet-derived growth factor (PDGF), a smooth musde growth factor. PDGF could also be released by both endothelial cells, macrophages, and platelets. Interferon-y (y-IFN) and lymphotoxin (LT), both of which are T cell lymphoklnes, could regulate growth and expression of several genes, including HLA-DR in both endothelial and smooth muscle cells. Together, these cytokines may have profound effects on growth and differentiation in the vessel wail. between these mechanisms in any given situation during lesion development. T cell activation may itself be regulated by apclipoprotein E-containing LDL, which thus could form a direct link between lipoprotein accumulation and immune activation.160 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.161 This could be due to an inhibition of T cell activation, resulting in an inhibition of monocytemacrophage activation and thereby loss of an important stimulus for intimai 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. 162163 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. 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G K Hansson, L Jonasson, P S Seifert and S Stemme Downloaded from http://atvb.ahajournals.org/ by guest on May 11, 2017 Arterioscler Thromb Vasc Biol. 1989;9:567-578 doi: 10.1161/01.ATV.9.5.567 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1989 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://atvb.ahajournals.org/content/9/5/567 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. 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