Biomedical subjects

I Nordøy

Publications and source records attributed to I Nordøy.

At least 19 recordsLinked to original sources

PubMed2004

Expression of matrix metalloproteinases in patients with Wegener's granulomatosis.

BACKGROUND: Enhanced activity of matrix metalloproteinases (MMPs) has been reported to have a pathogenic role in several diseases such as cancer and cardiovascular disorders, and seems also to play a part in certain autoimmune diseases. OBJECTIVE: To examine whether enhanced MMP activity may also have a role in the pathogenesis of Wegener's granulomatosis (WG). METHODS: In a study group of 15 patients with WG and 15 controls, plasma levels and gene expression were measured in freshly isolated peripheral blood mononuclear cells (PBMCs) of several MMPs and their endogenous inhibitors (that is, tissue inhibitors of metalloproteinases (TIMPs)) by enzyme immunoassays and RNase protection assay, respectively. RESULTS: Whereas patients with WG in remission had enhanced gene expression of several MMPs and TIMPs in PBMCs, those with active disease had a selective up regulation of MMP-2 and MMP-8 compared with healthy controls, and a down regulation of TIMP-1 and TIMP-3 compared with other patients with WG. Moreover, plasma levels of TIMP-1 and MMP-8 correlated significantly with C reactive protein levels, further supporting an association between activation of the MMP/TIMP system and disease activity in WG. Finally, these changes in MMP/TIMP expression in WG were accompanied by increased total MMP activity in PBMC supernatants, particularly in those with active disease, suggesting a matrix degrading net effect. CONCLUSION: These findings suggest that disturbed MMP and TIMP activity has a role in the pathogenesis of WG.

Adult↗

PubMed2003

Cytomegalovirus infection induces production of human interleukin-10 in macrophages.

Earlier findings have suggested that the balance between interleukin-10 and tumor necrosis factor alpha levels in serum may influence the outcome of cytomegalovirus infection in renal transplant recipients. Therefore, the aim of the present study was to investigate whether human cytomegalovirus induces interleukin-10 production in macrophages. Experiments using human cytomegalovirus (strain 2006), ultraviolet-inactivated cytomegalovirus, and mock-infected differentiated THP-1 cells with or without ganciclovir or monoclonal anti-tumor necrosis factor alpha antibodies were performed. Cytomegalovirus-infected cells produced significantly higher levels of human interleukin-10 mRNA and interleukin-10 than ultraviolet-inactivated cytomegalovirus or mock-infected cells. The addition of ganciclovir had little effect on interleukin-10 production. Anti-tumor necrosis factor alpha antibodies appeared to reduce the interleukin-10 levels. In conclusion, human cytomegalovirus infection of macrophages induces production of human interleukin-10. This requires viral entry, but not full viral replication.

Biomarkers↗

PubMed2003

CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells.

CXC-chemokines may be involved in atherogenesis. Herein we examined the possible role of CXC-chemokines in the inflammatory interactions between oxidized (ox-) low-density lipoprotein (LDL), platelets and peripheral blood mononuclear cells (PBMC) in 15 patients with coronary artery disease (CAD) without 'traditional' risk factors and 15 carefully matched controls. Our main findings were: (a) ox-LDL stimulated the release of the CXC-chemokines interleukin (IL)-8, ENA-78 and GRO-alpha from PBMC, particularly in CAD. (b) In platelets, ox-LDL induced release of ENA-78 and, when combined with SFLLRN, also of GRO-alpha, with significantly higher response in CAD. (c) Platelet-rich plasma, especially when costimulated with ox-LDL, enhanced the release of IL-8 from PBMC, particularly in CAD patients. (d) Freshly isolated PBMC showed markedly increased IL-8 mRNA expression in CAD patients. Our findings suggest enhanced inflammatory interactions between ox-LDL, platelets and PBMC in CAD patients involving CXC-chemokine related mechanisms, possible contributing to atherogenesis in these and other CAD patients.

Adult↗

PubMed2002

Immunophenotypic analyses of CD34(+) cell subsets in bone marrow from HIV-infected patients during highly- active antiretroviral therapy.

BACKGROUND: Because increased bone marrow lymphopoiesis might contribute to immunologic reconstitution during highly-active antiretroviral therapy (HAART), we examined the effect of HAART on CD34(+) cell subsets in bone marrow from HIV-infected patients. MATERIALS AND METHODS: In 12 HIV-infected patients, bone marrow and peripheral blood were collected before then 4 and 26 weeks after initiating HAART. Bone marrow in 28 HIV-seronegative controls was also examined. Immunophenotypic analyses of CD34(+) cell subsets in bone marrow were performed by flow cytometry. RESULTS: Our main findings in bone marrow were: (i) HIV-infected patients had increased proportions of CD34(+)cells expressing T- and B-cell markers before initiating HAART; (ii) in contrast, these patients had decreased proportions of CD34(+) cells expressing myeloid-associated markers; (iii) although HAART induced an increase in peripheral T-cell counts, the percentage of CD34(+)cells expressing T-cell markers tended to decrease during such therapy; (iv) HAART induced a decrease in serum IgG accompanied by a slight decrease in the proportion of CD34(+)cells expressing B-cell markers; (v) in contrast, HAART induced a significant increase in peripheral granulocyte counts, accompanied by a slightly increased proportion of CD34(+) cells expressing myeloid-associated molecules. CONCLUSION: Our findings are compatible with an HIV-related block in T-cell differentiation, leading to accumulation of T-cell progenitors in bone marrow, and such a block may be removed by HAART.

Adult↗

PubMed2001

Complex effects of interferon-alpha on the cytokine network in HIV infection--possible contribution to immunosuppression.

Since interleukin (IL-)2, IL-10 and IL-12 may contribute to the pathogenesis of human immune deficiency virus (HIV) infection we examined the effect of interferon (IFN)-alpha on these cytokines in cultures of various subsets of peripheral blood mononuclear cells (PBMC) in ten HIV-infected patients and ten healthy controls. Our main findings were: (1) IFN-alpha markedly enhanced IL-10 levels in a dose-dependent manner in both lipopolysaccharide (LPS)- and phytohaemagglutinin (PHA)-stimulated PBMC, as well as in anti-CD3- and anti-CD3/anti-CD28-stimulated T cells in both HIV-infected patients and controls. (2) In contrast, IFN-alpha had a downregulatory effect on IL-10 levels in Candida -stimulated PBMC,with particularly strong suppressive effect in HIV-infected patients. (3) Furthermore, IFN-alpha had a significant but modest stimulatory effect on IL-2 levels in PHA- and Candida -stimulated PBMC and anti-CD3-stimulated T cells. (4) IFN-alpha enhanced IL-12 levels in a dose-dependent manner in LPS-stimulated PBMC in both patients and controls. Our findings that IFN-alpha markedly enhanced IL-10 and modestly enhanced IL-2 and IL-12, suggest a net immunosuppressive effect of IFN-alpha in HIV-infected patients, possibly contributing to progression of immunodeficiency in these patients.

Adult↗

PubMed2000

Enhancement of lymphocyte proliferation induced by interleukin-12 and anti-interleukin-10 in HIV-infected patients during highly active antiretroviral therapy.

Based on the potentially important role of IL-10 and IL-12 in the pathogenesis of HIV infection, we have examined the effect of highly active antiretroviral therapy (HAART) on the production of these two cytokines, and whether addition of IL-12 or anti-IL-10 in vitro could improve the proliferative response in peripheral blood mononuclear cells (PBMC) from HIV-infected patients during such therapy. Our findings are: (i) After initiating HAART there were no significant changes in PHA- or MAC-PPD-stimulated IL-10 and IL-12 levels in PBMC supernatants in the patient group as a whole. (ii) However, while a decline in IL-10 synthesis was shown in patients with high baseline MAC-PPD- and PHA-stimulated IL-10 levels, IL-10 increased in patients with lower baseline levels. A similar pattern was seen for MAC-PPD-stimulated IL-12 levels. (iii) Exogenously added IL-12 and anti-IL-10 markedly and additively improved MAC-PPD-stimulated PBMC proliferation in vitro. Thus, a loss of cell-mediated immune response exists in HIV-infected patients also during apparently successful HAART and this can be significantly improved by addition of IL-12 and anti-IL-10, at least in vitro. These results suggest that further exploration of both IL-10 and IL-12 as targets for immunomodulating therapy in HIV-infected patients in addition to HAART might be important.

Adult↗

PubMed2000

Chemokines and soluble adhesion molecules in renal transplant recipients with cytomegalovirus infection.

Cytomegalovirus (CMV) infection is associated with leucocyte infiltration in various organs, which supports a role for chemokines and adhesion molecules in the pathogenesis of CMV infection. In a prospectively conducted study of renal transplant recipients, 10 patients with CMV disease, five patients with asymptomatic CMV infection and 10 patients who did not have any CMV infection were included. During CMV infection, and in particular during CMV disease, plasma levels of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) and the soluble adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and L-selectin increased and were positively correlated with the degree of CMV pp65 antigenaemia. Furthermore, a decrease in plasma levels of these chemokines and adhesion molecules was observed following ganciclovir therapy in the patients with CMV disease. This could suggest a role for these molecules in the pathogenesis of CMV infection.

Adult↗

PubMed2000

The role of the tumor necrosis factor system and interleukin-10 during cytomegalovirus infection in renal transplant recipients.

The effects of cytomegalovirus (CMV) infection on monocyte and T cell activation and the role of the tumor necrosis factor (TNF) system and interleukin (IL)-10 were studied in a prospective study of 25 renal transplant recipients. Ten patients developed CMV disease (group A), 5 developed asymptomatic infection (group B), and 10 did not have CMV infection (group C). During CMV disease (group A), there was evidence of both monocyte and T cell activation. All patients with CMV infection (groups A and B) showed increased activation of the TNF system, concomitant with an increase in plasma levels of IL-10. Patients with CMV disease (group A) had more marked manifestations of TNF activation and more moderate IL-10 increase than patients with asymptomatic CMV infection (group B), reflected in a higher plasma IL-10/TNF-alpha ratio in asymptomatic patients. Thus, the balance between TNF-alpha and IL-10 may be important in the development of CMV infection and CMV-related disease.

Adult↗

PubMed1999

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.

Adult↗

PubMed1999

Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency.

The molecular mechanisms underlying the T cell dysfunction often present in common variable immunodeficiency (CVI) are not established. cAMP-dependent protein kinase A type I (PKAI) is an important inhibitor of T cell proliferation after Ag stimulation. We therefore investigated the possibility that activation of PKAI may be involved in the development of T cell dysfunction in CVI. An exogenously added PKAI-selective antagonist (Rp-8-Br-cAMPS) induced a significant increase in anti-CD3-stimulated PBMC proliferation in 20 CVI patients compared with no effect in 15 controls. Purified T cells from 7 CVI patients with strictly defined T cell deficiency had elevated endogenous cAMP levels compared with controls. Treatment of T cells from these CVI patients with Rp-8-bromo-cAMP-phosphorothioate markedly improved anti-CD3-stimulated proliferation (up to 3.7-fold), particularly in CD4+ lymphocytes, reaching proliferation levels comparable to control values. No effect of cAMP antagonist on T cell proliferation was seen in controls. In these CVI patients, cAMP antagonist also increased IL-2 production in anti-CD3-stimulated T cells. However, exogenously added IL-2 at concentrations comparable to the achieved increase in IL-2 levels after addition of cAMP antagonist had no effect on T cell proliferation. Furthermore, the stimulatory effects of exogenously added IL-2 at higher concentrations and cAMP antagonist on T cell proliferation were additive. Our findings indicate that increased PKAI activation may be an important molecular basis for the T cell defect in CVI and suggest that the cAMP/PKAI system may be a potential molecular target for immunomodulating therapy in these patients.

Adult↗

PubMed1999

Administration of intravenous immunoglobulin (IVIG) in vivo--down-regulatory effects on the IL-1 system.

Modulation of the cytokine network may be of importance for the beneficial effects of therapy with IVIG seen in a wide range of immune-mediated disorders. In the present study we investigate the effect of IVIG administration in vivo on the IL-1 system in 12 patients with primary hypogammaglobulinaemia. Before IVIG infusion these patients had significantly elevated levels of IL-1alpha and IL-1beta both in plasma and in supernatants from peripheral blood mononuclear cells (PBMC) compared with healthy controls. After one bolus infusion with IVIG (0.4 g/kg) we found a significant change in the profile of the components of the IL-1 system: a marked increase in levels of IL-1 receptor antagonist (IL-1Ra) and neutralizing antibodies against IL-1alpha, a moderate decrease in levels of IL-1alpha, IL-1beta and soluble (s) IL-1 receptor type I and a significant increase in sIL-1 receptor type II levels. These changes were found both in plasma and in PBMC isolated after IVIG administration. Furthermore, pooled serum obtained after IVIG infusion suppressed lipopolysaccharide- and staphylococcal enterotoxin B-stimulated, but not phorbol myristate acetate-stimulated, release of IL-1alpha and IL-1beta from PBMC isolated from healthy controls. Finally, these changes in circulating levels of various IL-1 modulators after IVIG infusion appeared to cause a significantly impaired ability of IL-1 to stimulate PBMC for tumour necrosis factor-alpha release. Our findings suggest that IVIG administration may not only down-regulate the activity in the IL-1 system, but also hamper IL-1 stimulation of PBMC.

Adult↗

PubMed1999

Immunologic parameters as predictive factors of cytomegalovirus disease in renal allograft recipients.

Cytomegalovirus (CMV) disease is a major problem in renal transplant recipients, but few predictive markers of the disease are known. Several immunologic parameters of potential relevance for the defense against CMV were measured after renal transplantation in 25 patients before any manifestations of CMV infection occurred. In 10 patients who later developed CMV disease, plasma levels of interleukin-8 were significantly higher, whereas the levels of macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly lower than in 15 patients who did not develop CMV disease. Also, lower numbers of CD4+ and CD8+ lymphocytes were observed in patients who later had CMV disease. These findings were independent of previous rejection therapy and were particularly pronounced in patients with primary CMV infection. Interleukin-8 and MIP-1alpha may be predictive markers of CMV disease and could be of potential use in selecting patients for prophylactic treatment.

Adult↗

PubMed1998

Elevated circulating levels of C-C chemokines in patients with congestive heart failure.

BACKGROUND: Immunologic and inflammatory responses appear to play a pathogenic role in the development of congestive heart failure (CHF). Activation and migration of leukocytes to areas of inflammation are important factors in these immunologic responses. Because the C-C chemokines are potent chemoattractants of monocytes and lymphocytes and can modulate other functions of these cells (eg, generation of reactive oxygen species), we measured circulating levels of three C-C chemokines in CHF. METHODS AND RESULTS: Levels of macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein- 1alpha (MIP-1alpha), and RANTES (regulated on activation normally T-cell expressed and secreted) were measured by enzyme immunoassays in 44 patients with CHF and 21 healthy control subjects. CHF patients had significantly elevated levels of all chemokines with the highest levels in New York Heart Association class IV, and MCP-1 and MIP-1alpha levels were significantly inversely correlated with left ventricular ejection fraction. Elevated C-C chemokine levels were found independent of the cause of the heart failure, but MCP-1 levels were particularly raised in patients with coronary artery disease. Studies on cells isolated from peripheral blood suggested that platelets, CD3+ lymphocytes, and in particular, monocytes, might contribute to the elevated C-C chemokine levels in CHF. The increased MCP-1 levels in CHF were correlated with increased monocyte activity reflected in an enhancing effect of serum from CHF patients on O2-generation in monocytes, which was inhibited by neutralizing antibodies against MCP-1. CONCLUSIONS: This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.

Adult↗

PubMed1998

Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation.

Recent reports suggest a role for immunologic and inflammatory processes in the pathogenesis of congestive heart failure (CHF) and accelerated coronary artery disease (CAD) after heart transplantation (HT). The interaction between endothelial cells, leukocytes, and platelets involving various adhesion molecules may be of particular importance. We therefore measured serum levels of soluble(s) vascular cell adhesion molecule-1 (VCAM-1), sP-selectin, and sE-selectin in 34 patients with severe CHF (23 with CAD and 11 with idiopathic dilated cardiomyopathy) and in 20 healthy controls. Twenty of the patients were followed with serial measurements of these circulating adhesion molecules (CAMs) for up to 2 years after HT. Levels of all 3 CAMs were significantly elevated in patients with CHF compared with controls irrespective of the etiology of heart failure, with particularly high concentrations of sVCAM-1. After HT, different patterns in CAMs were found over time. Whereas there was a normalization of sE-selectin levels after HT, concentrations of sVCAM-1 also declined, but without normalization. In contrast, sP-selectin levels were persistently elevated, with the highest concentrations at the end of the study period. The persistent elevation of sP-selectin and the lack of normalization of sVCAM-1 levels were associated with persistently raised serum levels of tumor necrosis factor-alpha, and these findings were not related to either acute episodes of allograft rejection or intercurrent infections. These results support the notion that immunologic and inflammatory processes are important features of CHF. Furthermore, the persistently elevated levels of CAMs and tumor necrosis factor-alpha found up to 2 years after HT may reflect a state of persistent immune activation in these patients, possibly involved in the development of CAD after HT.

Adolescent↗

PubMed1998

Adhesion molecules in common variable immunodeficiency (CVID)--a decrease in L-selectin-positive T lymphocytes.

CVID is immunologically characterized by defective antibody production. Various additional immunological abnormalities have been reported, but little is known of the role of adhesion molecules in CVID. In 31 CVID patients serum levels of L-selectin (CD62L), vascular cell adhesion molecule-1 (VCAM-1) (CD106) and intercellular adhesion molecule-1 (ICAM-1) (CD54) were significantly elevated compared with controls. In 15 CVID patients investigated, the number of L-selectin-positive cells was significantly reduced in both CD4+ and CD8+ lymphocytes compared with controls, and these changes were observed in both CD45RA+ and CD45RO+ subsets. In CD19+ lymphocytes the percentage of ICAM-1+ cells was significantly increased compared with controls. Fifty percent of the patients had splenomegaly. These patients demonstrated even higher serum levels of adhesion molecules, a lower percentage of L-selectin-positive and a higher percentage of CD38+ cells in many T lymphocyte subsets compared with both other CVID patients and controls. Finally, in this patient group the percentage of L-selectin-positive CD19+ lymphocytes was significantly reduced compared with both other patients and controls. These findings indicate a state of ongoing T lymphocyte activation in CVID, especially in the subgroup of patients with splenomegaly, which may contribute to the impaired antimicrobial defence observed in these patients.

ADP-ribosyl Cyclase↗

PubMed1997

Modulation of lymphocyte and monocyte activity after intravenous immunoglobulin administration in vivo.

In 12 patients with primary hypogammaglobulinaemia we investigated the in vivo effect of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on lymphocyte subsets and monocytes in peripheral blood, on plasma levels of soluble factors reflecting monocyte and lymphocyte activity and on lymphocyte proliferation and generation of reactive oxygen species (ROS) from monocytes analysed in vitro. Several immunological changes were induced by IVIG infusion. First, there was a significant decrease in CD4+/CD8+ lymphocyte ratio in peripheral blood, reflecting a significant increase in circulating numbers of CD8+ lymphocytes. Second, although there was no significant change in plasma levels of soluble CD8 antigen, there was a significant decrease in soluble CD8 antigen/CD8+ lymphocyte ratio, suggesting a down-regulation of CD8+ lymphocyte activity. Third, there was a significant increase in plasma levels of neopterin, suggesting in vivo activation of monocytes/macrophages. Fourth, the was a down-modulation of mitogen-stimulated lymphocyte proliferation in vitro, and this down-regulation was significantly correlated with the increase in plasma neopterin levels. Finally, there was a significant decrease in zymosan-stimulated, but not in phorbol myristate acetate-stimulated, ROS generation from monocytes as evaluated by nitroblue tetrazolium reduction. The ability of IVIG administration in vivo to down-modulate lymphocyte proliferation and ROS generation from monocytes in patients with persistent immune activation may be relevant for the clinical effects of IVIG in a variety of immune-mediated disorders.

Adult↗

PubMed1997

Effects of intravenous immunoglobulin in vivo on abnormally increased tumor necrosis factor-alpha activity in human immunodeficiency virus type 1 infection.

The effect of a single bolus injection (0.4 g/kg) of intravenous immunoglobulin (IVIG) on the tumor necrosis factor (TNF) system in human immunodeficiency virus type 1 (HIV-1)-infected patients was investigated. At 140 h after infusion, there was a significant decrease in levels of TNF-alpha and a significant increase in levels of soluble TNF receptors (sTNFR) in both plasma and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). A rapid (within 1 h) decline in expression of membrane-bound TNF-alpha and p55-TNFR on PBMC persisted throughout the study. In contrast, there was an increased expression of membrane-bound p75-TNFR after 140 h. IVIG administration also resulted in significantly increased numbers of circulating CD4 lymphocytes, correlated with down-regulation of TNF-alpha activity in PBMC supernatants. Thus, down-regulation of the abnormally increased TNF-alpha activity may be achieved by IVIG administration. Studies evaluating the possible therapeutic role of long-term TNF-alpha suppression by IVIG may be warranted in HIV-1-infected patients.

Adult↗

PubMed1997

Interferon-alpha 2b therapy in low-activity hepatitis C: a pilot study.

BACKGROUND: Many patients with chronic hepatitis C have long periods of normal or near-normal liver enzyme levels, even though histologic alterations have been confirmed. The recommendation today is not to treat this patient group. METHODS: In a pilot study 23 hepatitis C virus (HCV) RNA-positive patients with alanine aminotransferase (ALAT) levels less than 1.5 times upper normal limits for at least 6 months on more than three occasions and with histologic liver abnormalities compatible with chronic hepatitis C were treated with 3 MU of interferon-alpha 2b three times a week for 6 months. RESULTS: Nine patients (39%) became HCV RNA-negative in serum during treatment, but only two (8.7%) remained so after 6 months' follow-up. Significantly more patients with genotype other than type 1 became HCV RNA-negative than patients with genotype 1 during treatment (P = 0.005). CONCLUSIONS: Patients with low-activity chronic hepatitis C have a response to interferon-alpha treatment similar to that of patients with increased ALAT levels. Genotype seems to influence the rate of response.

Adult↗