© 1996 American Heart Association, Inc.
Articles |
Effect of Immunization With Homologous LDL and Oxidized LDL on Early Atherosclerosis in Hypercholesterolemic Rabbits
the Atherosclerosis Research Center, Division of Cardiology and Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif (S.A., F.C., J.Y., B.C., P.K.S.); the Department of Cell and Molecular Biology, Karolinska Institutet (A.H.-N.); and King Gustaf Vth Research Institute, Department of Medicine, Karolinska Hospital (J.R., J.N.), Stockholm, Sweden.
Correspondence to Jan Nilsson, King Gustaf Vth Research Institute, Karolinska Hospital, 171 76 Stockholm, Sweden.
Abstract
Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% (P<.05) and 48% (P=NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions.
Key Words: atherosclerosis • autoimmunity • lipoproteins • oxidation
Several recent studies have demonstrated the existence of T lymphocytes in the atherosclerotic plaque.1 2 3 These cells often demonstrate markers of activation such as HLA-DR4 and very late activation antigen-15 and frequently colocalize with HLA-DR-expressing macrophages and smooth muscle cells.1 Taken together, these findings suggest the involvement of specific immune responses in the atherosclerotic process, but their precise biological role remains to be fully defined. Experimental studies in which animals have been immunized against foreign proteins have generally resulted in increased progression of atherosclerosis.6 7 Accordingly, it has been assumed that immune responses are atherogenic as a result of increased activity of inflammatory cells in the vessel wall. However, this concept has recently been challenged by studies demonstrating that immunosuppressive therapy increases atherosclerosis in cholesterol-fed rabbits8 and enhances neointima formation after balloon injury in rats.9
Data regarding the antigen specificity of T cells in the atherosclerotic plaque are limited. However, recent studies performed on T-cell clones established from human atherosclerotic plaques show that some clones recognize oxidatively modified LDL.10 The notion that oxidation of LDL makes the lipoprotein a target for the immune system is also supported by the existence of circulating autoantibodies against oxidized LDL11 12 13 14 and the fact that these antibodies bind to oxidized LDL present in plaques.15 Moreover, oxidized LDL has been shown to activate peripheral T cells in the presence of antigen-presenting cells in vitro.16 Oxidized LDL is highly cytotoxic17 18 and may promote the development of atherosclerosis by several mechanisms.19 A rapid clearance of oxidized LDL by antibody binding and Fc receptor uptake may thus serve to limit the damage produced by oxidized LDL particles in the arterial wall. Indeed, Palinski and coworkers20 recently reported that immunization of LDL receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherosclerosis. The present study confirms these findings in rabbits with diet-induced hypercholesterolemia with a lower level of immunization against copper-oxidized LDL.
Methods
Preparation of LDL and Oxidized LDL
New Zealand White rabbits with diet-induced hypercholesterolemia (total serum cholesterol levels of 800 to 1200 mg/dL) were killed by an intravenous overdose of fluanisone and Pentothal. Blood was drawn into precooled evacuated tubes containing Na2EDTA (1.4 mg/mL) from a catheter placed in the carotid artery. Plasma was then recovered by centrifugation at 1400g for 20 minutes at 1°C. The isolated plasma was adjusted to a density of 1.10 kg/L by addition of NaCl. A density gradient consisting of 3 mL of 1.10 kg/L density plasma and 3 mL of 1.065, 1.020, and 1.006 kg/L NaCl solutions, respectively, was then formed in cellulose nitrate tubes (Ultraclear tubes, Beckman) and centrifuged overnight at 4°C (Beckman L8-55 ultracentrifuge, 40 000 rpm) in a Beckman SW 40 swinging bucket rotor.21 The VLDL fraction was aspirated from the top 3 mL, and IDL+LDL was harvested from the next 3 mL of the tube. The EDTA was subsequently removed by dialysis against EDTA-free PBS. The protein content of the LDL preparation was determined as described by Lowry et al.22 The isolated LDL was then either stored in 20 µmol/L of the antioxidant butylated hydroxytoluene or oxidized by incubation in 5.0 µmol/L CuSO4/PBS for 18 hours at 37°C. The oxidized LDL showed increased mobility on agarose gel electrophoresis compared with LDL.
Experimental Animals and Treatment Groups
Young male New Zealand White rabbits with a mean weight of 3.5 kg were housed individually under conditions of 12-hour light/dark periods. The animals were fed standard rabbit pellets supplemented with 1% cholesterol and 3% peanut oil for the entire study period. On the first day of cholesterol feeding, 18 rabbits were immunized with 280 µg of LDL emulsified in 700 mg of adjuvant (AdjuPrime, Pierce), 18 rabbits were immunized with 280 µg oxidized LDL emulsified in 700 mg of adjuvant, and 18 rabbits received 700 mg of adjuvant/PBS. All immunizations were performed by subcutaneous injections at multiple sites. Reimmunization with an identical protocol was performed 3 weeks after the first injection. It was hypothesized that endogenously occurring antigens would further boost the immune response, and no additional immunizations were therefore performed. The decision to use AdjuPrime rather than Freund's complete adjuvant was based on earlier reports that immune reaction against heat shock protein present in Freund's complete adjuvant produces atherosclerosis in hypercholesterolemic rabbits.7
Four rabbits from each of the three treatment groups were killed by an intravenous overdose of fluanisone and Pentothal after 8 and 12 weeks, respectively. The remaining animals from each of the three treatment groups were killed after 16 weeks. Three animals in the adjuvant group and one animal immunized with LDL died during the study period. After the animals were killed, the aorta and iliac and femoral arteries were removed and immersed in 4% paraformaldehyde for 3 hours and then transferred to a solution of 15% sucrose in PBS and stored at 4°C overnight. The protocol for animal use was approved by Cedars-Sinai Institutional Animal Care and Use Committee.
Serum Cholesterol Measurement
Serum cholesterol levels were measured by an enzymatic technique (Sigma Chemical Co) at the beginning of the study and again when the animals were killed.
ELISA for Antibodies Against Oxidized LDL
Enzyme-linked immunosorbent assay (ELISA) microtiter plates (96 wells, Costar) were coated with coating buffer (0.2 mol/L sodium bicarbonate buffer, pH 9.4) containing 10 µg/mL of LDL or oxidized human LDL for 2 hours at 20°C (human LDL was isolated from healthy subjects by the same technique as described above for isolation of rabbit LDL). The coated wells were rinsed in washing buffer (PBS/0.1% BSA/0.05% Tween 20) and incubated with blocking buffer (PBS/1% BSA) for 1 hour at 20°C. Test sera were serially diluted in blocking buffer and added to the wells for overnight incubation at 20°C. The wells were then washed extensively with washing buffer and incubated with peroxidase-labeled goat anti-human IgG antibodies (diluted 1/4000 in blocking buffer) for 2 hours at 20°C. After they were repeatedly rinsed in washing buffer, the plates were developed by incubation with ABTS (2,2'-azino-bis-[3-ethylbenzothiazoline sulfonate]) for 30 minutes at 20°C and read in an ELISA reader at 405 nm. Oxidized LDL-specific antibody titers were calculated by subtracting binding to wells coated with LDL and expressed as units ([oxidized LDL absorbance-native LDL absorbance]x100). There was no significant difference in binding between uncoated wells and wells coated with native LDL, suggesting that no immune response occurred against unmodified LDL.
Immunohistochemistry and Morphometric Analysis
Starting at its proximal end, four 0.5-mm-long arterial segments were taken at 5-mm intervals from the proximal third of the descending aorta. Similarly, two 0.5-mm-long sections were taken at 5-mm intervals from the middle third of the descending aorta starting at its proximal end, and two 0.5-mm-long sections were taken at 5-mm intervals from the distal third of the descending aorta starting at its proximal end. All tissue specimens were mounted in OCT medium for cryosectioning. Then 10-µm-thick sections were mounted on polysialylated glass slides, rinsed in PBS, and incubated with blocking serum for 1 hour. They were then incubated with antibodies against rabbit macrophages (RAM 11; DAKO), rabbit T lymphocytes (L 11/135), rabbit class II antigen (2C4), or smooth muscle cell-specific 
-actin (DAKO) dissolved in PBS/0.1% Triton X-100 for 18 hours in a humidifying chamber. Controls included an irrelevant antibody as well as omission of the primary antibody. The sections were subsequently rinsed in PBS, incubated with biotinylated anti-mouse IgG for 60 minutes, rinsed in PBS, and incubated with alkaline phosphatase-labeled biotin streptavidin complexes for 2 hours. The cells were finally incubated with alkaline phosphatase substrate solution for 30 minutes in darkness and counterstained with hematoxylin.
A semiquantitative analysis of the immunohistochemistry staining was performed as described by Galis et al.23 Consistent positive staining was recorded as 2, variable or weak staining as 1, and no staining as 0. Results are presented as mean±SD of the mean score of all animals killed after 16 weeks of diet for RAM 11 and -actin antibodies and on four animals in each group for the L11/135 and 2C4 antibodies.
Cross sections for morphometric analysis were stained with hematoxylin. Plaque areas were determined with the Optimas image analysis program, as described.24 Briefly, each slide contained two cross sections from the proximal third of the aorta, one cross section from the mid third of the aorta, and one cross section from the distal third of the aorta. All intimal lesions in each cross section were outlined, and the lesion area was quantified by image analysis. Lesion area in the proximal aorta was expressed as mean lesion area of the two cross sections. Total lesion area was calculated by adding the mean area of the two proximal cross sections to the lesion areas of the mid and distal sections. The final values for each animal represent the mean of two such slides containing cross sections taken at different levels in the respective thirds (see above). Values for interobserver and intraobserver variability of these measurements were less than 5%.
Statistical Analysis
Values are presented as mean±SD. One-way ANOVA followed by the Scheffé's F test was used for between-group analysis. A corrected value of P<.05 was considered significant.
Results
The mean serum cholesterol level before initiation of a cholesterol-rich diet was 40 mg/dL or below. After 8 weeks or more of diet, cholesterol levels were above 1000 mg/dL. There were no significant differences in serum cholesterol levels between any of the treatment groups (Table 1
).
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Antibodies Against Oxidized LDL
No circulating antibodies against oxidized LDL were detected before cholesterol feeding. After 16 weeks of cholesterol feeding, all animals had developed antibodies against oxidized LDL. However, the antibody titer was twofold higher in animals immunized with LDL or oxidized LDL compared with animals given adjuvant alone (Fig 1).
|
) and after 16 weeks of diet in rabbits given adjuvant/PBS (
) or immunized with native (
) or copper-oxidized LDL (
) were determined as described in "Methods." Values represent mean±SE of animals immunized with adjuvant/PBS (n=5), LDL (n=7), or copper-oxidized LDL (n=8).
Atherosclerotic Lesion Formation
After 8 weeks of cholesterol feeding, small fatty streak-like plaques were detected in two of the adjuvant-treated rabbits, in two LDL-immunized rabbits, and in three oxidized LDL-immunized rabbits. At 12 weeks, all animals had small fatty lesions. At 8 and 12 weeks, there was no difference in mean lesion area between the three treatment groups (Fig 2). At 16 weeks, total lesion area in the analyzed cross sections (sum of the mean plaque area in the proximal, mid, and distal parts of the aorta) was 4.08±3.60 mm2 in rabbits given adjuvant alone, 1.21±0.98 mm2 in rabbits immunized with LDL (P=.052 versus adjuvant alone), and 2.32±1.30 mm2 (P=NS) in rabbits immunized with oxidized LDL (Fig 2). A marked decrease in lesion area was found in the proximal third of the aorta in rabbits immunized with LDL compared with rabbits given adjuvant alone (3.08±2.50 mm2 versus 0.82±0.58 mm2; P=.029; Fig 3). The lesion area in the proximal third of the aorta was also reduced in animals immunized with oxidized LDL (1.61±0.84 mm2), but this difference did not reach statistical significance (P=.17). Overall, immunizations with both LDL and oxidized LDL were associated with a tendency toward decreased plaque area in all regions of the aorta (Fig 3). There were no significant correlations between antibody levels and plaque area in any of the groups or in the entire experimental group. Moreover, there were no significant correlations between serum cholesterol levels and plaque area.
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Immunohistochemistry and Cellular Composition
Macrophages appeared to be the dominating cell type in the lesions of rabbits with diet-induced atherosclerosis (Fig 4A and 4B). In larger plaques, numerous smooth muscle cells were also present. These were preferentially located toward the luminal part of the lesion, and structures resembling fibrous caps were present in many lesions (Fig 4C). Class II antigen expression occurred with a distribution similar to that of macrophages (Fig 4D and 4E). Lymphocytes were present in most lesions but were substantially fewer than the macrophages and smooth muscle cells. They were usually located in the shoulder region of the plaques and appeared to be more frequent in smaller than in larger lesions (Fig 4F). There were no differences in cell composition or class II antigen expression between the different groups (Table 2).
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Discussion
The role of the immune system in atherosclerosis has been receiving increasing attention. It is now recognized that atherosclerotic plaques are characterized not only by the presence of "nonspecific" inflammatory reactions but also by more specific T cell-mediated immune responses.25 How these two processes interact remains to be fully clarified. Oxidative modification of LDL particles in the vascular wall may play a particularly important role in this context. Oxidation of LDL is associated with formation of cytotoxic compounds such as oxysterols, peroxides, lysophospholipids, and aldehydes,26 27 and the cell damage caused by these substances is likely to induce a nonspecific inflammatory response. This response may be further enhanced by the proinflammatory effects that have been attributed to minimally modified or low levels of fully oxidized LDL.19 28 T lymphocytes isolated from human atherosclerotic plaques are specifically activated by oxidized LDL,10 suggesting that a cell-mediated immune response against these particles is taking place in the lesions. This reaction may serve to further promote the inflammatory process in the lesions but may also help to clear oxidized LDL from the extracellular space, thus limiting its nonspecific inflammatory effect.
The results of the present study demonstrate that low-level immunization of hypercholesterolemic rabbits with homologous LDL and homologous copper-oxidized LDL reduces intimal lesion formation in response to a cholesterol diet. These results confirm previous observations by Palinski and coworkers20 demonstrating that immunization of LDL receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces the formation of atherosclerotic plaques and supports the notion that an immune response against modified lipoproteins has a protective role in the early stages of atherosclerosis. In our study immunization with copper-oxidized LDL reduced mean lesion area of cross sections from different parts of the aorta by 40% compared with a 30% reduction of the percent aortic surface covered by atherosclerotic lesions by immunization with malondialdehyde-modified LDL in the study by Palinski and coworkers. Hence, the net effect of immunization against oxidized LDL appears to be similar, although different animal models, different antigens, different modes of immunizations, and different techniques for evaluation were used in these two studies.
Another important difference between the study by Palinski et al20 and ours is the antibody levels obtained. In the former study reimmunizations were performed every month throughout a 6-month study period, resulting in a 10-fold increase in antibody levels compared with animals given adjuvant alone. In our study the rabbits were reimmunized only once, resulting in a mere 2-fold increase in antibody levels compared with controls. The decision to use this protocol was based on the assumption that diet-induced hypercholesterolemia would result in arterial accumulation of oxidized LDL, which in itself would further propagate the immune response. Indeed, sera taken from normocholesterolemic rabbits before immunization did not contain antibodies against oxidized LDL, whereas antibodies against oxidized LDL were present in all animals kept on a hypercholesterolemic diet for 16 weeks even without immunization with LDL or oxidized LDL. These findings support the hypothesis that diet-induced hypercholesterolemia is associated with oxidative modification of LDL in vivo and development of an autoimmune response against epitopes present on these modified lipoprotein particles. Similar observations have been made in LDL receptor-deficient mice, which develop marked hypercholesterolemia and autoantibodies against oxidized LDL when fed a cholesterol-rich diet.13 However, although the present protocol was less effective in inducing a humoral immune response, the net effect on arterial plaque formation was similar. It is not clear how this observation should be interpreted. One possibility is that the increase in antibody levels obtained in our study was sufficient to inhibit lesion formation, but the lack of correlation between antibody levels and lesion area does not support this concept. Moreover, the observation that in LDL receptor-deficient mice antibody levels against oxidized LDL correlate with disease progression also suggests that antibody levels may be a poor marker of an antiatherogenic effect of immune response against modified lipoproteins.
Another possibility is that cell-mediated immunity plays a more important role than the humoral immunity in the antiatherogenic response to immunization with oxidized LDL. Several recent studies have supported this concept. Suppression of T-cell function by cyclosporin A in rabbits with diet-induced hypercholesterolemia results in enhanced development of atherosclerosis without affecting serum levels of antibodies against malondialdehyde-modified LDL.8 Moreover, class I major histocompatibility complex-deficient C57BL/6 mice, which lack cytolytic T cells and have an impaired natural killer cell activity, develop a threefold increase in aortic lesions when fed a high-cholesterol diet.29 Finally, removal of T cells with monoclonal antibodies has been shown to enhance neointima formation after balloon injury of rat aortas.9
An unexpected observation in the present study was that immunization with LDL was as effective as immunization with oxidized LDL in inhibiting atherosclerosis. Since homologous LDL was used in the immunizations, we did not anticipate that it would evoke an immune response. However, at 16 weeks antibody levels against oxidized LDL in animals immunized with LDL were comparable to the animals immunized with oxidized LDL, suggesting that an immune response against oxidized LDL was also induced in the group immunized with LDL. The most probable explanation of this phenomenon is that the LDL became modified during the immunization procedure. The LDL used in this study was isolated from severely hypercholesterolemic rabbits. This LDL is markedly enriched in larger IDL-like particles and has a markedly abnormal structure compared with LDL from normocholesterolemic rabbits.30 This IDL-LDL fraction is approximately four times more susceptible to oxidative modification in vitro than human LDL (J. Regnström et al, unpublished data). Moreover, in humans LDL from hypercholesterolemic subjects demonstrates early signs of oxidative modification, as assessed by an increased hydroperoxide content.31 It is thus possible that the hypercholesterolemic rabbit LDL preparation used for immunization in our study contained modifications leading to appearance of antigen epitopes. Another possibility is that the LDL becomes modified when trapped with the adjuvant polymer in lymphatic tissue. The observation that rabbits immunized with LDL have increased levels of antibodies against oxidized LDL does indeed strongly suggest that an oxidative modification did take place and that the mechanisms for the antiatherogenic effects of LDL and oxidized LDL immunizations were the same. If the modification of native LDL occurred in vivo, it may represent a more physiological modification, which may explain why immunization with native LDL was even more effective than immunization with copper-oxidized LDL in preventing lesion formation in response to high-cholesterol diet.
In summary, the present findings suggest that the presence of an immune reaction against oxidized LDL may help to inhibit the formation of early atherosclerotic lesions in hypercholesterolemic rabbits. However, further studies are required to elucidate whether immune reactions against oxidized LDL are also beneficial in humans and in more advanced stages of the disease.
Acknowledgments
This study was supported by grants from the American Heart Association, the Swedish Medical Research Council (8311), the Swedish Heart and Lung Foundation, the Tore Nilssons Fund, the Swedish Society of Medicine and King Gustav V's 80th Birthday Fund, and the Grand Foundation of Los Angeles. We thank Drs Göran Hansson, Joseph Witztum, and Wulf Palinski for helpful discussions.
Received December 18, 1995; revision received March 12, 1996; References
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G. Stoll and M. Bendszus Inflammation and Atherosclerosis: Novel Insights Into Plaque Formation and Destabilization Stroke, July 1, 2006; 37(7): 1923 - 1932. [Abstract] [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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X. Zhou, A.-K. L. Robertson, C. Hjerpe, and G. K. Hansson Adoptive Transfer of CD4+ T Cells Reactive to Modified Low-Density Lipoprotein Aggravates Atherosclerosis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 864 - 870. [Abstract] [Full Text] [PDF]
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E Toubi and Y Shoenfeld Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality? Lupus, September 1, 2005; 14(9): 665 - 669. [Abstract] [PDF]
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 C. Meisinger, J. Baumert, N. Khuseyinova, H. Loewel, and W. Koenig Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for Acute Coronary Heart Disease Events in Apparently Healthy, Middle-Aged Men From the General Population Circulation, August 2, 2005; 112(5): 651 - 657. [Abstract] [Full Text] [PDF]
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C. J. Binder, P. X. Shaw, M.-K. Chang, A. Boullier, K. Hartvigsen, S. Horkko, Y. I. Miller, D. A. Woelkers, M. Corr, and J. L. Witztum Thematic review series: The Immune System and Atherogenesis. The role of natural antibodies in atherogenesis J. Lipid Res., July 1, 2005; 46(7): 1353 - 1363. [Abstract] [Full Text] [PDF]
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I. Goncalves, M.-L. M. Gronholdt, I. Soderberg, M. P.S. Ares, B. G. Nordestgaard, J. F. Bentzon, G. N. Fredrikson, and J. Nilsson Humoral Immune Response Against Defined Oxidized Low-Density Lipoprotein Antigens Reflects Structure and Disease Activity of Carotid Plaques Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1250 - 1255. [Abstract] [Full Text] [PDF]
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J. Nilsson Regulating Protective Immunity in Atherosclerosis Circ. Res., March 4, 2005; 96(4): 395 - 397. [Full Text] [PDF]
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X. Zhou, A.-K. L. Robertson, M. Rudling, P. Parini, and G. K. Hansson Lesion Development and Response to Immunization Reveal a Complex Role for CD4 in Atherosclerosis Circ. Res., March 4, 2005; 96(4): 427 - 434. [Abstract] [Full Text] [PDF]
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F. J. Tinahones, J. M. Gomez-Zumaquero, L. Garrido-Sanchez, E. Garcia-Fuentes, G. Rojo-Martinez, I. Esteva, M. S. R. de Adana, F. Cardona, and F. Soriguer Influence of age and sex on levels of anti-oxidized LDL antibodies and anti-LDL immune complexes in the general population J. Lipid Res., March 1, 2005; 46(3): 452 - 457. [Abstract] [Full Text] [PDF]
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J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
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 K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis J. Immunol., November 15, 2004; 173(10): 5901 - 5907. [Abstract] [Full Text] [PDF]
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A. Schiopu, J. Bengtsson, I. Soderberg, S. Janciauskiene, S. Lindgren, M. P.S. Ares, P. K. Shah, R. Carlsson, J. Nilsson, and G. N. Fredrikson Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis Circulation, October 5, 2004; 110(14): 2047 - 2052. [Abstract] [Full Text] [PDF]
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C. A. Reardon, E. R. Miller, L. Blachowicz, J. Lukens, C. J. Binder, J. L. Witztum, and G. S. Getz Autoantibodies to OxLDL fail to alter the clearance of injected OxLDL in apolipoprotein E-deficient mice J. Lipid Res., July 1, 2004; 45(7): 1347 - 1354. [Abstract] [Full Text] [PDF]
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J. Karvonen, M. Paivansalo, Y. A. Kesaniemi, and S. Horkko Immunoglobulin M Type of Autoantibodies to Oxidized Low-Density Lipoprotein Has an Inverse Relation to Carotid Artery Atherosclerosis Circulation, October 28, 2003; 108(17): 2107 - 2112. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, M. Ares, B. Cercek, K.-Y. Chyu, P. K. Shah, and J. Nilsson Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 872 - 878. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, I. Soderberg, M. Lindholm, P. Dimayuga, K.-Y. Chyu, P. K. Shah, and J. Nilsson Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 879 - 884. [Abstract] [Full Text] [PDF]
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G. K. Hansson Vaccination Against Atherosclerosis: Science or Fiction? Circulation, September 24, 2002; 106(13): 1599 - 1601. [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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 Y Sherer and Y Shoenfeld Atherosclerosis Ann Rheum Dis, February 1, 2002; 61(2): 97 - 99. [Abstract] [Full Text] [PDF]
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF]
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C. Monaco, F. Crea, G. Niccoli, F. Summaria, D. Cianflone, R. Bordone, G. Bellomo, and A. Maseri Autoantibodies against oxidized low density lipoproteins in patients with stable angina, unstable angina or peripheral vascular disease; pathophysiological implications Eur. Heart J., September 1, 2001; 22(17): 1572 - 1577. [Abstract] [PDF]
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S. Stemme Plaque T-Cell Activity : Not So Specific? Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1099 - 1101. [Full Text] [PDF]
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J. Hulthe, O. Wiklund, E. Hurt-Camejo, and G. Bondjers Antibodies to Oxidized LDL in Relation to Carotid Atherosclerosis, Cell Adhesion Molecules, and Phospholipase A2 Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 269 - 274. [Abstract] [Full Text] [PDF]
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J. Hulthe, L. Bokemark, and B. Fagerberg Antibodies to Oxidized LDL in Relation to Intima-Media Thickness in Carotid and Femoral Arteries in 58-Year-Old Subjectively Clinically Healthy Men Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 101 - 107. [Abstract] [Full Text] [PDF]
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X. Zhou, G. Caligiuri, A. Hamsten, A. K. Lefvert, and G. K. Hansson LDL Immunization Induces T-Cell-Dependent Antibody Formation and Protection Against Atherosclerosis Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 108 - 114. [Abstract] [Full Text] [PDF]
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 R. Wu, C. Lemne, U. de Faire, and J. Frostegard Antibodies to Lysophosphatidylcholine Are Decreased in Borderline Hypertension Hypertension, January 1, 2001; 37(1): 154 - 159. [Abstract] [Full Text] [PDF]
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 F. G. de Oliveira, C. L. Rossi, M. G. de Oliveira, M. J.A. Saad, and L. A. Velloso Effect of vitamin E supplementation on antibody levels against malondialdehyde modified LDL in hyperlipidemic hamsters Cardiovasc Res, August 18, 2000; 47(3): 567 - 573. [Abstract] [Full Text] [PDF]
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P. M. Morganelli, S. M. Kennedy, and T. I. Mitchell Differential effects of interferon-{gamma} on metabolism of lipoprotein immune complexes mediated by specific human macrophage Fc{gamma} receptors J. Lipid Res., March 1, 2000; 41(3): 405 - 415. [Abstract] [Full Text]
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M. Fukumoto, T. Shoji, M. Emoto, T. Kawagishi, Y. Okuno, and Y. Nishizawa Antibodies Against Oxidized LDL and Carotid Artery Intima-Media Thickness in a Healthy Population Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 703 - 707. [Abstract] [Full Text] [PDF]
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E. Ahmed, J. Trifunovic, B. Stegmayr, G. Hallmans, and A. K. Lefvert Autoantibodies Against Oxidatively Modified LDL Do Not Constitute a Risk Factor for Stroke : A Nested Case-Control Study Stroke, December 1, 1999; 30(12): 2541 - 2546. [Abstract] [Full Text] [PDF]
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B. Metzler, M. Mayr, H. Dietrich, M. Singh, E. Wiebe, Q. Xu, and G. Wick Inhibition of Arteriosclerosis by T-Cell Depletion in Normocholesterolemic Rabbits Immunized With Heat Shock Protein 65 Arterioscler. Thromb. Vasc. Biol., August 1, 1999; 19(8): 1905 - 1911. [Abstract] [Full Text] [PDF]
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A. Shaish, J. George, B. Gilburd, P. Keren, H. Levkovitz, and D. Harats Dietary ß-Carotene and {alpha}-Tocopherol Combination Does Not Inhibit Atherogenesis in an ApoE–Deficient Mouse Model Arterioscler. Thromb. Vasc. Biol., June 1, 1999; 19(6): 1470 - 1475. [Abstract] [Full Text] [PDF]
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N. Leitinger, A. D. Watson, S. Y. Hama, B. Ivandic, J.-H. Qiao, J. Huber, K. F. Faull, D. S. Grass, M. Navab, A. M. Fogelman, et al. Role of Group II Secretory Phospholipase A2 in Atherosclerosis : 2. Potential Involvement of Biologically Active Oxidized Phospholipids Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1291 - 1298. [Abstract] [Full Text] [PDF]
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J George, D Harats, B Gilburd, Y Levy, P Langevitz, and Y Shoenfeld Atherosclerosis-related markers in systemic lupus erythematosus patients: The role of humoral immunity in enhanced atherogenesis Lupus, March 1, 1999; 8(3): 220 - 226. [Abstract] [PDF]
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J. George, Y. Shoenfeld, A. Afek, B. Gilburd, P. Keren, A. Shaish, J. Kopolovic, G. Wick, and D. Harats Enhanced Fatty Streak Formation in C57BL/6J Mice by Immunization With Heat Shock Protein-65 Arterioscler. Thromb. Vasc. Biol., March 1, 1999; 19(3): 505 - 510. [Abstract] [Full Text] [PDF]
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A. C Newby and A. B Zaltsman Fibrous cap formation or destruction -- the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation Cardiovasc Res, February 1, 1999; 41(2): 345 - 360. [Abstract] [Full Text] [PDF]
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R. Wu, U. de Faire, C. Lemne, J. L. Witztum, and J. Frostegard Autoantibodies to OxLDL Are Decreased in Individuals With Borderline Hypertension Hypertension, January 1, 1999; 33(1): 53 - 59. [Abstract] [Full Text] [PDF]
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S. Freigang, S. Horkko, E. Miller, J. L. Witztum, and W. Palinski Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1972 - 1982. [Abstract] [Full Text] [PDF]
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J. George, A. Afek, B. Gilburd, M. Blank, Y. Levy, A. Aron-Maor, H. Levkovitz, A. Shaish, I. Goldberg, J. Kopolovic, et al. Induction of Early Atherosclerosis in LDL-Receptor–Deficient Mice Immunized With ß2-Glycoprotein I Circulation, September 15, 1998; 98(11): 1108 - 1115. [Abstract] [Full Text] [PDF]
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J. Hulthe, J. Wikstrand, A. Lidell, I. Wendelhag, G. K. Hansson, and O. Wiklund Antibody Titers Against Oxidized LDL Are Not Elevated in Patients With Familial Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., August 1, 1998; 18(8): 1203 - 1211. [Abstract] [Full Text] [PDF]
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K. E Matthys, C. E Van Hove, M. M Kockx, L. J Andries, N. Van Osselaer, A. G Herman, and H. Bult Exposure to oxidized low-density lipoprotein in vivo enhances intimal thickening and selectively impairs endothelium-dependent dilation in the rabbit Cardiovasc Res, January 1, 1998; 37(1): 239 - 246. [Abstract] [Full Text] [PDF]
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K. E. Matthys, C. E. Van Hove, M. M. Kockx, L. J. Andries, N. Van Osselaer, A. G. Herman, and H. Bult Local Application of LDL Promotes Intimal Thickening in the Collared Carotid Artery of the Rabbit Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2423 - 2429. [Abstract] [Full Text]
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 A. D. Watson, N. Leitinger, M. Navab, K. F. Faull, S. Horkko, J. L. Witztum, W. Palinski, D. Schwenke, R. G. Salomon, W. Sha, et al. Structural Identification by Mass Spectrometry of Oxidized Phospholipids in Minimally Oxidized Low Density Lipoprotein That Induce Monocyte/Endothelial Interactions and Evidence for Their Presence in Vivo J. Biol. Chem., May 23, 1997; 272(21): 13597 - 13607. [Abstract] [Full Text] [PDF]
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 H. M. Dansky, S. A. Charlton, M. M. Harper, and J. D. Smith T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse PNAS, April 29, 1997; 94(9): 4642 - 4646. [Abstract] [Full Text] [PDF]
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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