ovalbumin and Arteriosclerosis

Antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation in the course of adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Nicotine has been shown to increase the growth of atherosclerotic lesions. Therefore, we investigated whether nicotine can stimulate APCs and their T cell-stimulatory capacity using human monocyte-derived DCs and murine bone marrow-derived DCs as APCs.. Nicotine dose-dependently (10(-8) to 10(-4) mol/L) induced DC expression of costimulatory molecules (ie, CD86, CD40), MHC class II, and adhesion molecules (ie, LFA-1, CD54). Moreover, nicotine induced a 7.0-fold increase in secretion of the proinflammatory T(H)1 cytokine interleukin-12 by human DCs. These effects were abrogated by the nicotinic receptor antagonist alpha-bungarotoxin and mecamylamine, respectively. The effects of nicotine were mediated in part by the phosphorylation of the PI3 kinase downstream target Akt and the mitogen-activated kinases ERK and p38 MAPK. Nicotine-stimulated APCs had a greater capacity to stimulate T-cell proliferation and cytokine secretion, as documented by mixed lymphocyte reactions and ovalbumin-specific assays with ovalbumin-transgenic DO10.11 mice. In a murine model of atherosclerosis, nicotine significantly enhanced the recruitment of DCs to atherosclerotic lesions in vivo.. Nicotine activates DCs and augments their capacity to stimulate T-cell proliferation and cytokine secretion. These effects of nicotine may contribute to its influence on the progression of atherosclerotic lesions.

Topics: Animals; Antigens, CD; Arteriosclerosis; B7-2 Antigen; CD40 Antigens; Cell Adhesion Molecules; Cell Division; Cells, Cultured; Dendritic Cells; Dose-Response Relationship, Drug; Histocompatibility Antigens Class II; Humans; Immunity, Cellular; Interleukin-12; Lymphocyte Culture Test, Mixed; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Transgenic; Mitogen-Activated Protein Kinases; Monocytes; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Ovalbumin; Peptide Fragments; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Nicotinic; T-Lymphocytes; Up-Regulation

T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.. Clones of ovalbumin (OVA)-specific Tr1 cells expanded in vitro were administered intraperitoneally (106 cells per mouse) with their cognate antigen (50 microg of OVA subcutaneously in complete Freund's adjuvant [CFA]) to female apolipoprotein E-knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (P<0.0001), a decrease in the production of interferon-gamma (P<0.001), and an increase in interleukin-10 production (P<0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A-stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls (P=0.002 to P<0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice.. Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.

Topics: Adoptive Transfer; Animals; Apolipoproteins E; Arteriosclerosis; Bystander Effect; Cells, Cultured; Cholesterol; Clone Cells; Cytokines; Female; Freund's Adjuvant; Immunoglobulin E; Immunoglobulin G; Immunosuppression Therapy; Interferon-gamma; Interleukin-10; Lymph Nodes; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Spleen; T-Lymphocytes; Th1 Cells

We have previously shown that low density lipoprotein receptor-deficient (LDL-RD) mice immunized with beta2-glycoprotein I (beta2GPI; a target of autoimmune anticardiolipin antibodies) developed enhanced early atherosclerosis, when fed a normal chow diet. The current study was undertaken to evaluate the effect of immunization with beta2GPI and the addition of a high fat diet on the progression of atherosclerosis in the apolipoprotein E (ApoE)-deficient mouse. Six-week-old female ApoE-deficient mice (n = 10) were immunized subcutaneously with either human beta2GPI or with ovalbumin, both emulsified in complete Freund's adjuvant and fed a high fat diet for 6 weeks. The beta2GPI-immunized mice were found to develop accelerated atherosclerosis when compared with their ovalbumin-immunized littermates (aortic lesion area of 137,500 +/- 13,801 vs. 72,444 +/- 14,465 microm2, respectively; p = 0.0067). The beta2GPI-immunized mice developed high titers of anti-beta2GPI antibodies, 10 days after the procedure, which were sustained until the sacrifice. LDL extracted from both study groups displayed similar susceptibility to ex vivo oxidation. These results confirm our previous study in which we found increased atherosclerosis in beta2GPI-immunized LDL-RD mice fed a chow diet. In the current study we show that the proatherogenic effect of beta2GPI immunization is maintained despite high cholesterol levels and is not associated with increased susceptibility of LDL to ex vivo oxidation.

Topics: Animals; Antibodies; Antibody Specificity; Apolipoproteins E; Arteriosclerosis; beta 2-Glycoprotein I; Dietary Fats; Female; Glycoproteins; Humans; Immunization; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Receptors, Lipoprotein; Risk Factors

A study was carried out to establish an animal model that would be suitable for evaluating the role of the diet in immune cell-mediated atherogenesis. Brown Norway rats were initially treated with hypervitamin D2 for 4 days and then fed on an atherogenic diet for 3 months, during which period the rats were either immunized with ovalubumin plus Al(OH)3 (OVA group) or with Al(OH)3 alone (control group) every 3 weeks. Aortic lesions were mainly composed of foam cells, the lesions evaluated by the intimal thickness of the ascending aorta being more severe in the OVA group than in the control group. The OVA group, in comparison with the control group, showed prominently increased serum levels of OVA-specific IgG and rat chymase, an indicator of mast cell degranulation. The intimal thickness was positively correlated with the level of chymase. Immunization had no effect on the serum lipid levels. These results support the hypothesis that mast cells play a role in the early stage of atherosclerosis and suggest that this animal model could be useful for evaluating the role of the diet in immune-related atherogenesis.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Aorta; Arteriosclerosis; Cholesterol; Chymases; Diet, Atherogenic; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ergocalciferols; Image Processing, Computer-Assisted; Immunoglobulin G; Ovalbumin; Phospholipids; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Reagins; Serine Endopeptidases; Serine Proteinase Inhibitors; Triglycerides

Immunization with beta2-glycoprotein I (beta2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of beta2GPI immunization on the progression of atherosclerosis.. In the first experiment, 3 groups of LDL receptor-deficient (LDL-RD) mice (n=15 per group) were immunized with either beta2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All beta2GPI-immunized mice developed high titers of anti-beta2GPI antibodies as well as a specific lymph node proliferation to beta2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the beta2GPI-immunized mice (mean aortic lesion, 26 000+/-5700 microm2) in comparison with their ovalbumin-immunized (mean, 3000+/-1099 microm2; P<0.01) and nonimmunized (mean, 2250+/-700 microm2; P<0.01) littermates. The average lesion size in the beta2GPI-immunized mice fed an atherogenic diet (mean, 98 000+/-8305 microm2) was larger than the ovalbumin-immunized mice (mean, 81 250+/-12 933 microm2; P=NS) or the nonimmunized controls (mean, 75 625+/-7281 microm2; P=NS). The atherosclerotic plaques in the beta2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice.. The results of the present study provide the first direct evidence for the proatherogenic effect of ss2GPI immunization and establish a new model for immune-mediated atherosclerosis.

Topics: Animals; Antibodies; Antibody Specificity; Antigen-Antibody Complex; Aortic Valve Stenosis; Apolipoproteins; Arteriosclerosis; Bacterial Proteins; beta 2-Glycoprotein I; Body Weight; CD4-Positive T-Lymphocytes; Chaperonin 60; Chaperonins; Cholesterol, LDL; Diet; Female; Glycoproteins; Immunization; Immunohistochemistry; Lymph Nodes; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Ovalbumin; Receptors, LDL

Intimal thickening in the aorta and carotid artery of rats was induced by repeated intraperitoneal injections of ovalbumin, 2.5 mg/kg BW, given weekly 5 times after initial subcutaneous sensitization, and/or feeding with a cholesterol-rich diet. The intimal thickening was apparent in immune-challenged rats fed with either a cholesterol-rich or a basal diet (p less than 0.01), whereas it was mild in non-immunized rats fed a cholesterol-rich diet. The ultrastructural changes in the thickened intima were characterized by leukocytic (mainly monocytic) adhesion and migration, and minor endothelial cell damage. Morphometric evaluation of leukocyte adhesion to the intima of the thoracic aorta revealed that the immunized rats fed either a cholesterol-rich or a basal diet showed greater leukocytic adhesion (p less than 0.01 and p less than 0.001, respectively) than that in non-immunized rats fed a cholesterol-rich diet, which in turn also showed an increased degree of leukocyte adhesion (p less than 0.05) than control rats. This immunological approach to the arteriosclerotic process could explain the earlier and more severe arteriosclerosis found in patients with immunological disorders, and the development of arteriosclerosis in the absence of hypercholesterolemia, hypertension and other risk factors.

Topics: Animals; Antibody Formation; Aorta; Arteriosclerosis; Carotid Arteries; Cell Adhesion; Cell Movement; Cholesterol, Dietary; Endothelium, Vascular; Immune System; Injections, Intraperitoneal; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Ovalbumin; Rats; Rats, Inbred Strains