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G K Hansson

Publications and source records attributed to G K Hansson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Evidence for antigen-driven T-cell response in unstable angina.

BACKGROUND: Activation of T cells and macrophages has been associated with unstable angina (UA), but whether this reflects specific immune responses remains unclear. METHODS AND RESULTS: We analyzed the repertoire and the length of complementarity-determining region 3 of the T-cell receptor (TCR) beta-chain variable (BV) gene segments of activated lymphocytes in 23 patients with UA, 13 patients with chronic stable angina (CSA), and 6 normal control subjects. We also tested the proliferation of systemic T cells in response to autologous coronary plaque proteins, oxidized LDL, and Chlamydia pneumoniae as candidate antigens, in vitro. The activated T cell-TCRBV repertoire was perturbed in 13 (57%) of 23 UA patients versus 3 (23%) of 13 CSA patients (P=0.016) and was restricted to 6 (28%) of 21 expanded TCRBV families; all were significantly higher in UA than in CSA patients. At least one monotypic or oligotypic activated TCRBV population was found in 15 (65%) of 23 UA patients and in 3 (23%) of 13 CSA patients (P<0.001). Finally, T cells from UA patients, but not from CSA patients or normal control subjects, proliferated in response to autologous proteins from coronary culprit lesions and/or to oxidized LDL. CONCLUSIONS: Our findings suggest that the T-cell response observed in UA patients is antigen-driven and directed to antigens contained in the culprit coronary atherosclerotic plaques.

Angina, Unstable↗
PubMed2000

Retinoic acid inhibits nitric oxide synthase-2 expression through the retinoic acid receptor-alpha.

Retinoids are multipotent modulators of cellular functions and suppress cytokine-induced production of nitric oxide (NO) in several cell types. We have explored the mechanisms by which retinoic acid (RA) regulates NO production in rat aortic smooth muscle cells (VSMC), which express NOS2 in response to proinflammatory cytokines. RA inhibited interleukin-1beta (IL-1beta)-induced NOS2 mRNA expression and NO production. These effects were attenuated by the retinoic acid receptor (RAR) antagonist CD3106, indicating that they were mediated through retinoic acid receptors (RARs). The synthetic retinoid agonists CD336 (which specifically binds RARalpha) and CD367 (which binds all RARs) but not agonists specific for RARbeta, RARgamma, or RXRs reduced IL-1beta-induced NOS2 expression and NO production. When transfecting VSMC with a 1570-bp NOS2 promoter fragment fused to a luciferase reporter gene, the NOS2 promoter activity was inhibited by RA. These results indicate that retinoids modulate NO production in VSMC via RARalpha, which inhibits the transcription of the NOS2 gene.

Animals↗
PubMed2000

Gene expression of inflammatory mediators in different chambers of the human heart.

BACKGROUND: Inflammatory genes may be unevenly expressed in different heart chambers. METHODS: Biopsies were taken simultaneously from the right atrium (RA), left atrium (LA), and left ventricle (LV) of 19 patients before cardioplegic arrest during open heart surgery. The mRNA expression of tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1 (ET-1), E-selectin (CD62E), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD18, and CD25 was evaluated with semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Expression of TNFalpha mRNA was higher in RA than LA and LV (p<0.05), whereas IL-1beta was more expressed in LA than RA (p<0.05), which was higher than LV (p<0.0001). There were no significant regional differences in the expression of ICAM-1, CD62E, CD25, iNOS, and eNOS. CD18 was higher in RA than LA (p<0.05); ET-1 was more expressed in RA than LV (p<0.04). Patients with stable angina had no expression of eNOS. CONCLUSIONS: Gene expression of inflammatory mediators was detected in the hearts of patients with different cardiovascular disorders, and was unevenly distributed in different heart chambers. Cardiac biopsies should be taken from the same site.

CD18 Antigens↗
PubMed2000

Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NFkappaB and AP-1.

OBJECTIVE: Unstable angina may improve the clinical outcome of acute myocardial infarction, but increases the morbidity and mortality of open heart surgery. We hypothetized that unstable angina influences the myocardium, and investigated the expression of the inducible heat shock protein 72 (HSP72), constitutive HSP73, and endothelial nitric oxide synthase (eNOS), and activation of the transcription factors NFkappaB and AP-1 in cardiac tissue. METHODS: Biopsies were taken from the right atrium of 15 patients with unstable and 15 with stable angina undergoing coronary artery bypass grafting. Immunoblotting with monoclonal antibodies against HSP72, HSP73, and eNOS were performed on protein extracts, while nuclear proteins were assessed by electromobility shift assay. RESULTS: When calculating the optical density of the bands, patients with unstable angina had more than twice as much HSP72 and eNOS as stable patients (P<0.005), while HSP73 was similar in both groups. Nuclear translocation of NFkappaB and AP-1 was found in patients with anginal pain shortly before surgery, but not in stable patients or in patients without symptoms for 4 days or more prior to surgery. CONCLUSIONS: HSP72 and eNOS, which may be associated with cardioprotection in ischemic preconditioning, are increased in atrial tissue of patients with unstable angina. Activation of NFkappaB and AP-1, which regulate a battery of inflammatory genes, was found in hearts of unstable patients. NFkappaB activation may induce a myocardial proinflammatory state, possibly making the unstable myocardium more susceptible to the inflammation induced by open heart surgery.

Aged↗
PubMed2000

Immunomodulation of atherosclerosis: myth and reality.

Atherosclerosis is an inflammatory disease which displays features of immune activation both locally and systemically. In the present review, we discuss the evidence for immune activation in human disease and experimental models, and survey candidate antigens associated with atherosclerosis. Studies of atherosclerosis in genetic models of immunodeficiency are analysed, as well as immunomodulating therapies and immunization protocols. Based on recent research, it is concluded that immunomodulation represents an interesting approach to the development of new prevention and treatment methods for atherosclerosis.

Animals↗
PubMed2000

Expression of cyclo-oxygenase-2 in human atherosclerotic carotid arteries.

OBJECTIVES: the preventive effect of acetylsalicylic acid in cardiovascular disease may be due to inhibition of platelet aggregation mediated by COX-1, but may in addition be due to anti-inflammatory effects by inhibition of COX-2. The objective of this study was to analyse the expression of COX-1 and COX-2 in atherosclerotic and healthy vascular walls. DESIGN: the expression COX-1 and COX-2 was analysed in biopsies from human atherosclerotic carotid arteries and from healthy mammary arteries and saphenous veins. MATERIALS: vascular biopsies were obtained from patients undergoing carotid endarterectomy or coronary bypass surgery. METHODS: RT-PCR was used for mRNA analysis and for localization of proteins we used immunohistochemistry. RESULTS: COX-2 was found in atherosclerotic plaques: in macrophages, in some smooth muscle cells and in endothelial cells of small vessels in the lesions. In non-atherosclerotic blood vessels, COX-2 was detected in the endothelium of the vasa vasorum in the adventitia. COX-1 was found in the endothelium in healthy and in atherosclerotic vessels. CONCLUSIONS: the expression of COX-2 by inflammatory and vascular cells in atherosclerotic arteries suggests that products of this enzyme may be important in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed2000

The role of adaptive immunity in atherosclerosis.

Atherosclerosis is an inflammatory disease induced by a lipid metabolic disturbance at sites of hemodynamic strain in the vasculature. Studies in both man and experimental animal models show an involvement of innate and adaptive immune mechanisms in the disease process. Our recent studies in apoE-knockout mice show that the level of hypercholesterolemia affects the functional properties of the immune response. Modulating immune activity by injections of polyclonal immunoglobulins inhibits disease progression, suggesting that immunomodulation may be useful to treat atherosclerosis. Analysis of T cell receptor (TCR) mRNA in atherosclerotic lesions shows expansions of T cells expressing TCR-V beta 6, a receptor type that is also expressed by T cells recognizing oxidized low density lipoprotein (oxLDL). This suggests that oxLDL is an autoantigen that induces strong, local T cell responses in the plaque. Further characterization of this and other candidate antigens, such as heat shock proteins and macromolecular components of Chlamydia pneumoniae, may provide important information on which specific interference with the disease process could be based.

Animals↗
PubMed2000

Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu(2+) and Zn(2+).

Pyrrolidine dithiocarbamate (PDTC) has been found to induce or inhibit apoptosis in different cell types. Here we show that PDTC dose-dependently reduced the viability of rat smooth muscle cells (rSMC), human fibroblasts, and endothelial cells at low but not at high cell density. Endothelial cells were least sensitive, fibroblasts showed a medium sensitivity, and rSMC showed a high sensitivity to PDTC-mediated cell death. An early reduction in the mitochondrial membrane potential indicated a rapid onset of apoptosis in rSMC. Apoptosis was further confirmed by annexin V staining and DNA fragmentation analysis. Gel shift analysis demonstrated increased nuclear factor (NF)-kappaB activity in high-density rSMC compared with low-density cells. NF-kappaB has recently been shown to regulate the induction of anti-apoptotic proteins. Although PDTC is widely used as an inhibitor for NF-kappaB and a radical scavenger, our data show that PDTC rather enhanced NF-kappaB activity and, alone or in combination with menadione, induced oxygen radical generation. Notably, PDTC failed to reduce rSMC viability in medium without Cu(2+) or Zn(2+), and addition of Cu(2+) or Zn(2+) resulted in a dose-dependent increase in PDTC-induced cell death. Addition of both Cu(2+) and Zn(2+) showed synergistic effects. Our results indicate that the induction of apoptosis by PDTC requires Cu(2+) and Zn(2+) and is dependent on cell type and density. Such differential effects may have implications for studies of PDTC as an anti-atherosclerotic or immunomodulatory drug.

Animals↗
PubMed2000

Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice.

T cells are present in atherosclerotic lesions at all stages of development. They exhibit activation markers and are particularly prominent at sites of plaque rupture. This suggests that T-cell-mediated immune responses are involved in the pathogenesis of atherosclerosis. Antigen-specific T cells reactive with oxidized lipoproteins and heat shock proteins have been isolated from plaques, indicating that local activation and clonal expansion might occur. To analyze different stages of atherosclerosis, we have used a murine model. Targeted deletion of the apolipoprotein E gene results in severe hypercholesterolemia and spontaneous atherosclerosis, with lesions containing large numbers of T cells and macrophages. We have analyzed mRNA for T-cell antigen receptors (TCRs) from aortic fatty streaks, early fibrofatty plaques, and advanced fibrofatty plaques of such mice. Polymerase chain reaction amplification of complementarity-determining region 3 (CDR3 region) of TCRs was followed by spectratyping of fragment lengths. This analysis detected all types of variable (V) segments with a gaussian distribution of CDR3 in lymph nodes. In contrast, a restricted heterogeneity was found in atherosclerotic lesions, with expansion of a limited set of Vbeta and Valpha segments and a monotypic or oligotypic CDR3 spectrum in each lesion. Vbeta6 was expressed in all lesions; Vbeta5.2, Vbeta16, Valpha34s, and Valpha9, in the majority of lesions; and Vbeta6, Vbeta5.2, and Valpha34S, in lesions at all 3 stages of development. The strongly skewed pattern of the CDR3 region in the TCR is indicative of oligoclonal expansions of T cells and suggests the occurrence of antigen-driven T-cell proliferation in atherosclerosis.

Animals↗
PubMed2000

Induction of neonatal tolerance to oxidized lipoprotein reduces atherosclerosis in ApoE knockout mice.

BACKGROUND: In the course of atherosclerosis, humans and apolipoprotein (apoE) Knockout (KO) mice exhibit an active cell-mediated and humoral immune process, both at the systemic level and within atheromata. Low density lipoproteins (LDL) infiltrate the vascular wall, where they are oxidatively modified. This oxidative modification may generate new epitopes for which tolerance is not achieved during ontogenesis. Such epitopes could constitute new targets for autoreactive immune responses that may have a physiopathological role in disease development. MATERIALS AND METHODS: Exposing mice to high dose of antigens during thymic T-cell education induces immunological tolerance to the administered antigens. We injected newborn apoE KO mice with oxidized LDL. They were fed a cholesterol-rich diet and aortic atherosclerosis, cell-mediated immune response, and T-cell repertoire were analyzed after 5 months. RESULTS: Injection of oxidized LDL at birth reduced not only the immune response to oxidized LDL, but also susceptibility to atherosclerosis in apoE mice. Injection of oxidized LDL induced T-cell tolerance due to clonal deletion, rather than anergy of the reactive T cells. The T-cell repertoire of apoE KO mice was affected by the development of the disease, whereas tolerization normalized it. CONCLUSIONS: This study demonstrates that the immune response against oxidized LDL has a deleterious role in atherogenesis and that a fine-tuning of this response could modify the course of the disease.

Animals↗
PubMed1999

Nitric oxide metabolites in CSF of patients with MS are related to clinical disease course.

In this study, we have analyzed the stable metabolites of nitric oxide (NO), nitrite and nitrate, in the CSF of patients with MS, lymphocytic meningitis, and in healthy control subjects. Patients with MS with an active disease course exhibited increased CSF nitrite levels compared with patients with stable MS and healthy control subjects, whereas CSF nitrate levels did not differ between these groups. High CSF levels of both metabolites were seen in patients with meningitis. These data indicate that CSF nitrite levels may reflect clinical disease activity in MS.

Humans↗
PubMed1999

Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice.

Myocardial infarction is linked to atherosclerosis, yet the sequence leading from silent coronary atherosclerosis to acute myocardial infarction has remained unclear. Here we show that hypercholesterolemic apolipoprotein E-/- low density lipoprotein receptor-/- mice develop not only coronary atherosclerosis but also myocardial infarction. Exposure of mice to mental stress or hypoxia led to acute ischemia, which, in a large proportion of the mice, was followed by electrocardiographic changes, leakage of troponin T, and loss of dehydrogenase from the myocardium, all indicative of acute myocardial infarction. Apoptotic death of cardiomyocytes was followed by inflammation and fibrosis in the heart. All these pathological changes could be prevented by a blocker of the endothelin type A receptor. Thus, stress elicits myocardial infarction through endothelin receptor signaling in coronary atherosclerosis caused by hypercholesterolemia.

Animals↗
PubMed1999

Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells.

Apoptosis is important in normal development as well as in diseases such as atherosclerosis. However, the regulation of apoptosis is still not completely understood. We now show that the transcription factor nuclear factor-kappaB (NF-kappaB) controls the induction of apoptosis in human and rat vascular smooth muscle cells (SMCs). SMCs in high-density culture exhibited a high NF-kappaB activity and were insensitive to induction of apoptosis. Inhibition of NF-kappaB by adenovirus-mediated overexpression of its inhibitor IkappaBalpha caused a marked increase in cell death at low but not high cell density. Elevating endogenous IkappaBalpha levels by inhibiting its degradation with proteasomal inhibitors resulted in induction of apoptosis in low-density SMCs, as detected by increased binding of annexin V, reduced mitochondrial membrane potential, and increased hypodiploid DNA. In high-density cultures, protection against apoptosis was associated with the expression of inhibitor of apoptosis protein-1 (IAP-1). Transfer of IkappaBalpha reduced human IAP-1 mRNA levels, which suggested that IAP-1 is transcriptionally regulated by NF-kappaB. This was confirmed through identification of a motif with NF-kappaB-like binding activity in the human IAP-1 promoter region. Moreover, antisense inhibition of IAP-1 sensitized high-density SMCs to the induction of cell death. Together, our data imply that SMCs at high density are protected by an antiapoptotic mechanism that involves increased expression of NF-kappaB and IAP-1. Interference with pathways that control the susceptibility to programmed cell death may be helpful in the treatment of diseases where dysregulation of apoptosis is involved, eg, atherosclerosis and restenosis.

Animals↗
PubMed1999

The macrophage scavenger receptor type A directs modified proteins to antigen presentation.

Scavenger receptors constitute a family of cell surface receptors that internalize endotoxins, oxidized low-density lipoproteins (oxLDL) and other proteins with clustered negative charges for degradation in macrophages. They were recently proposed to play a role in antigen presentation but the type of scavenger receptor involved in this process has not been known. In this report, we have examined the cellular immune responses to modified proteins in mice lacking the SR-A scavenger receptor (SRAKO) and their wild-type (ICR) controls. While spleen cells of ICR mice immunized with maleylated murine serum albumin (Mal-MSA) exhibit strong proliferative responses to the antigen, no such responses were found in SRAKO mice. However, addition of SR-A+ antigen-presenting cells from ICR mice unmasked proliferative responses to Mal-MSA in spleen cultures of immunized SRAKO mice. Similarly, addition of SR-A+ antigen-presenting cells was necessary to detect T cell responses in spleen cultures of oxLDL-immunized SRAKO mice. This indicates that SR-A can mediate uptake of modified antigens for presentation to antigen-specific T cells. The fact that cellular immunity developed in SRAKO mice implies that other scavenger receptor(s) also internalize modified antigens for presentation in vivo. These observations show that scavenger receptors participate in immune recognition of oxidized protein antigens; this system may be important for recognition of damaged macromolecules but could also play a role in autoimmunity.

Animals↗
PubMed1999

Inflammation and immune response in atherosclerosis.

Atherosclerosis is an inflammatory disease with a significant autoimmune component. Studies using transgenic murine models have clarified that recruitment of mononuclear leukocytes through vascular leukocyte-adhesion molecules and chemokines, differentiation of monocytes to macrophages, and endocytosis through scavenger receptors all are of decisive importance for atherosclerosis in hypercholesterolemic mice. T and B cells modulate disease progression and lesion development is reduced in mice lacking adaptive immunity. In particular, local immune responses eliciting Th1 effector mechanisms appear to be proatherogenic, whereas protective immune responses can be induced by immunization with oxidized low-density lipoprotein. Thus, innate immunity is necessary for atherosclerosis, whereas adaptive immunity is an important modulator of disease development.

Animals↗
PubMed1999

Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.

The atherosclerotic lesion contains large numbers of macrophages and T lymphocytes. This suggests that a cellular immune response may take place in the lesion, and oxidized lipoproteins, heat shock proteins, and micro-organisms have been implied as candidate antigens. However, the effector mechanisms elicited by this response have been largely unclear. We have therefore analyzed endarterectomy specimens by immunohistochemistry and reverse transcription-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleukin-2 and interferon-7, were found in a large proportion of plaques (IL-2 in 50% and interferon-gamma in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleukin-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaques by immunohistochemistry, mRNA for interleukin-4 in 10% and for interleukin-5 in 40% by PCR). This demonstrates the presence of a predominantly pro-inflammatory, Th1-type T cell response in atherosclerosis. This conclusion was further supported by the expression of the pro-inflammatory cytokine, interleukin-1 by plaque macrophages and endothelial cells. In addition, the chemokine interleukin-8 and the macrophage differentiation-stimulating cytokine, granulocyte-monocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitment and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transforming growth factor-beta1-3 and its carrier protein, latent TGF-beta binding protein, were found in large amounts in all plaques. Together, these results show that a pro-inflammatory, Thl type cellular immune response takes place in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the lesion.

Arteriosclerosis↗
PubMed1999

Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice.

Estrogens and immunity against LDL could be important in atherogenesis. Herein, we describe the development of atherosclerotic lesions and cellular immune responses to modified LDL in male and female apoE knockout (E0) mice over time, and the effect of 17beta-estradiol on atherosclerosis-related cellular immunity. Animals were studied after 16 or 48 weeks of normocholesterol diet. Aortic lesions, lymphocyte populations, and the cellular immune response against modified LDL, with or without 17beta-estradiol, were analyzed. Atherosclerotic lesions were larger and more advanced in young female than in male E0 mice. In older mice, no significant difference in lesion size or maturity was discerned between males and females. In spleen cell cultures of young females, addition of 17beta-estradiol induced a proliferative T-cell response to oxidized LDL, while no such effect was seen in males. In similar cultures from old E0 mice, T-cells from female animals were activated by oxidized LDL even in the absence of exogenous estrogens. These data show important sex differences in the development of atherosclerosis. They suggest that these differences may be related to sex differences in the cellular immune responses to the atherosclerosis-related autoantigen, oxidized LDL.

Age Factors↗