Biomedical subjects

L Nagelkerken

Publications and source records attributed to L Nagelkerken.

At least 19 recordsLinked to original sources

PubMed2005

Soluble vascular cell adhesion molecule (VCAM) is associated with treatment effects of interferon beta-1b in patients with secondary progressive multiple sclerosis.

BACKGROUND: Subcutaneous IFNbeta-1b (Betaferon) is an established immunomodulatory treatment for relapsing remitting MS and active secondary progressive multiple sclerosis (SPMS). It modulates cytokine and adhesion molecule expression but long term in vivo effects of IFNbeta-1b on the immune system are not known in multiple sclerosis. OBJECTIVE: To address the effects of IFNbeta-1b on serum levels for soluble adhesion molecules and cytokine receptors from MS patients. METHODS: Serial blood samples were obtained from 40 patients of the frequent MRI subgroup (20 patients each from the placebo and the IFNbeta-1b treatment group), participating in the European multi-center clinical trial with IFNbeta-1b for secondary progressive MS, at regular intervals for up to 36 months. Soluble adhesion molecules (sVCAM, sICAM-1, sL-Selectin) as well as TNF-receptor I and II were analysed in the serum of patients by enzyme linked immunosorbent assays (ELISAs). Monthly brain MRI was performed in 34 of these patients (16 patients from the placebo and 18 from the IFNbeta-1b group) during months 1-6 and 19-24 to monitor disease activity as assessed by newly occurring gadolinium (Gd) enhancing lesions. RESULTS: An early and significant increase in sVCAM and sTNF-RII serum levels was detected in 16 out of 20 patients (80 %) treated with subcutaneous IFNbeta-1b already at month 1 but was absent in all but one patient during placebo treatment (p < 0.01). Raised sVCAM and TNF RII serum levels during months 1-6 inversely correlated with less MRI activity in the 19-24 months treatment interval in the IFNa-1b treatment group ( p = 0.0093 for TNF-RII; p = 0.047 for VCAM). CONCLUSIONS: sVCAM and sTNF RII levels in the serum of SPMS patients are increased during IFNbeta-1b therapy and may at least in part explain some of the treatment effects, like reduced immune cell transmigration.

Adult↗

PubMed2005

A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by Etomoxir.

BACKGROUND: The dogma in psoriasis is that due to pathogen-induced inflammatory responses, an autoreactive immune response is induced that leads to tissue destruction. However, this model might be too simplistic. Literature data suggest that the expression of enzymes crucial for fatty acid oxidation is upregulated in the skin of patients with psoriasis compared with healthy individuals. OBJECTIVES: To examine the influence of fatty acid oxidation on psoriasis with regard to expression and activity of the key enzyme in fatty acid oxidation, carnitine palmitoyltransferase-1 (CPT-1) and the effect of the CPT-1 inhibitor, Etomoxir. METHODS: Experiments were performed with homogenates of lesional and healthy skin, fibroblast cultures and a model of human psoriatic skin transplanted on immune-deficient BNX mice. RESULTS: CPT-1 was highly active in lesional skin. Etomoxir was able to block CPT-1 activity in skin, implying that this antagonist may have the potential to suppress psoriasis when administered topically. In the mouse model, Etomoxir had an antipsoriatic effect that was at least as good as that of betamethasone, as evidenced by reduction of epidermal thickness, keratinocyte proliferation and differentiation. CONCLUSIONS: We conclude that fatty acid metabolism and in particular CPT-1 may be an excellent target for treatment of psoriasis.

Animals↗

PubMed2004

Osteopontin levels and increased disease activity in relapsing-remitting multiple sclerosis patients.

Osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within multiple sclerosis (MS) lesions. Recently, we demonstrated that OPN plasma levels were elevated in active relapsing-remitting (RR) MS patients. In this longitudinal study, a trend was observed for OPN serum levels in relation to clinical exacerbations. Moreover, OPN protein levels were significantly elevated 1 month prior to increase of gadolinium (Gd)-enhancing lesion number, whereas no relation was observed between OPN levels and increase in Gd-enhancing lesion volume. Although no robust relation between OPN and disease activity was observed, these data suggest that OPN levels are elevated prior to increased disease activity in RR MS patients.

Adult↗

PubMed2003

Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.

Adjuvants, Immunologic↗

PubMed2001

Cytokine and IL-12 receptor mRNA discriminate between different clinical subtypes in multiple sclerosis.

Little is known about the involvement of cytokines in the pathogenesis of primary progressive (PP) multiple sclerosis (MS). We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF-alpha, IFN-gamma, IL-10, IL-4, TGF-beta, IL-12Rbeta1, and IL-12Rbeta2 mRNA expression in unstimulated white blood cells showed significant differences between relapsing-remitting (RR), secondary progressive (SP) and PP MS patients, and healthy controls. All clinical subtypes showed unique mRNA expression patterns as compared to the controls. Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-beta mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels. Both in PP and SP patients, IFN-gamma and IL-10 mRNA were decreased compared to RR patients and controls. PP patients were unique in that they showed decreased IL-12Rbeta1 mRNA. In conclusion, our data show that the assessment of cytokine (receptor) mRNA profiles is useful to discriminate between the different clinical subtypes and suggest that different cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.

Adult↗

PubMed2001

LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone.

Several causes have been held responsible for the chronic fatigue syndrome (CFS), including an altered hypothalamus-pituitary-adrenal gland (HPA)-axis activity, viral infections and a reduced Th1 activity. Therefore, it was investigated whether the regulation of IL-10 is different in CFS. LPS-induced cytokine secretion in whole blood cultures showed a significant increase in IL-10 and a trend towards a decrease in IL-12 as compared with healthy controls. In patients and controls, IL-12 secretion was equally sensitive to suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive in CFS-patients. In controls, IL-10 and IL-12 secretion were inversely correlated with free serum cortisol (r=-0.492, p<0.02 and r=-0.434, p<0.05, respectively). In CFS, such an inverse correlation was found for IL-12 (r=-0.611, p<0.02) but not for IL-10 (r=-0.341, ns). These data are suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS.

Adolescent↗

PubMed2001

Interferon-beta in multiple sclerosis: altering the balance of interleukin-12 and interleukin-10?

Interferon-beta is a remarkably pleiotropic molecule. Antiviral, pro- and antiproliferative, pro- and antiapoptotic, and complex immunoregulatory activities have all been described. The precise mechanism(s) that underlie the beneficial effects of interferon-beta in multiple sclerosis remain poorly understood; this has hindered progress in the search for more effective therapies. An increasing body of literature supports the hypothesis that interferon-beta-mediated changes in the production and activities of the immunoregulatory cytokines interleukin-12 and interleukin-10 are important to the therapeutic benefits of interferon-beta in multiple sclerosis. These data are reviewed here.

Animals↗

PubMed2001

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors.

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR). METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro. RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

Adolescent↗

PubMed2000

Contrasting responses to interferon beta-1b treatment in relapsing-remitting multiple sclerosis: does baseline interleukin-12p35 messenger RNA predict the efficacy of treatment?

Interferon (IFN)-beta treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18, tumor necrosis factor-alpha (TNFalpha), IFNgamma, IL-10, IL-4, or transforming growth factor-beta in unstimulated whole blood of 26 RR-MS patients changed during 6 months of IFNbeta-1b treatment. In these patients, a significant change was found in TNFalpha mRNA, whereas changes in IL-12 receptor-beta2 and IL-10 mRNA showed a trend. IFNbeta-1b-related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR-MS patients classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNbeta-1b treatment with respect to IL-10, TNFalpha, and IL-18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFalpha and IL-18 mRNA as well as a transient increase in IL-10 mRNA. Baseline levels of IL-12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patients under investigation.

Adult↗

PubMed2000

Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome.

It is increasingly recognized that glucocortiocoids (GCs) can have subtle modulatory effects in immunoregulation rather than having generalized immunosuppressive effects. GCs suppress Th1 cells and cellular immunity, but may favor Th2 responses and humoral immunity. The chronic fatigue syndrome (CFS) appears to be associated with a disturbed HPA-axis. Moreover, CFS patients show several immunological changes suggestive of decreased cellular immunity. It is postulated herein that in CFS patients a decreased Th1/Th2 balance may be the result of selective effects of GC on the IL-10/IL-12 regulatory circuit.

Fatigue Syndrome, Chronic↗

PubMed1999

Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)-12 (p40 and p35), tumor necrosis factor-alpha, interferon-gamma, and IL-10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing-remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL-12p40 and decreased levels of IL-10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL-12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL-12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL-12p40 mRNA. In RR MS, IL-10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL-10 mRNA levels constitutively, suggesting that IL-10 plays an important role in the control of disease progression.

Adult↗

PubMed1999

IFN-beta modulates specific T cell responses in vitro but does not affect Experimental Autoimmune Encephalomyelitis in the SJL mouse.

In this study, mouse recombinant IFN-beta was shown to favor PLP139-151-specific Th2 responses in vitro, by inhibiting IFN-gamma production and stimulating IL-4 and IL-10 production. IFN-beta (5000 U/day) failed to prevent the development or severity of EAE induced with PLP139-151. Whereas efficacy of IL-10 was found in the B. pertussis assisted but not in the pertussigen-assisted EAE model, both models appeared insensitive to IFN-beta. Also the combination of (suboptimal) IL-10 and IFN-beta appeared ineffective in inhibiting disease. However, the PLP139-151-specific IL-10 production by T cells from these mice appeared significantly more sensitive to the stimulatory effect of IFN-beta in vitro. It is concluded that despite its Th2 promoting effects, IFN-beta is not effective in inhibiting EAE in this study.

Animals↗

PubMed1998

Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro.

Antigen-presenting cells are thought to modulate the development of Th1 and Th2 cells by the secretion of interleukin-10 (IL-10) and IL-12. Because glucocorticoids (GC) favor the development of Th2 responses, we determined whether dexamethasone (DEX) and hydrocortisone (HC) have differential effects on lipopolysaccharide-induced IL-10 and IL-12 production in whole-blood cultures. Significant inhibition of IL-12(p40) and IL-12(p70) was found with 10(-8) mol/L and 10(-9) mol/L DEX respectively, whereas IL-10 was relatively insensitive or even stimulated. Accordingly, the expression of IL-12(p40) and IL-12(p35) mRNA was more sensitive to DEX than IL-10 mRNA. The glucocorticoid receptor (GR) antagonist RU486 enhanced IL-12 production and largely abrogated the inhibition of IL-12 by GC, indicating that this suppression was mainly GR-mediated. High concentrations of RU486 were inhibitory for IL-10, suggesting that GC may exert a positive effect on IL-10. In the presence of neutralizing anti-IL-10 antibodies, DEX was still capable of IL-12 suppression whereas RU486 still enhanced IL-12 production, indicating that GC do not modulate IL-12 via IL-10 exclusively. Taken together these results indicate that GC may favor Th2 development by differential regulation of IL-10 and IL-12.

Antigen-Presenting Cells↗

PubMed1998

CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone.

A disturbed hypothalamus-pituitary-adrenal gland axis and alterations at the immune system level have been observed in patients with chronic fatigue syndrome (CFS). Glucocorticoids are known to modulate T cell responses; therefore, purified CD4 T cells from CFS patients were studied to determine whether they have an altered sensitivity to dexamethasone (DEX). CD4 T cells from CFS patients produced less interferon-gamma than did cells from controls; by contrast, interleukin-4 production and cell proliferation were comparable. With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower DEX concentration was needed to achieve 50% inhibition of interleukin-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients. Surprisingly, interferon-gamma production in patients and controls was equally sensitive to DEX. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids might explain an altered immunologic function in CFS patients.

Adult↗

PubMed1998

Role of Th1 and Th2 cells in autoimmune demyelinating disease.

Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), whereas Th2 cells contribute to recovery from disease. A major determinant in the development of Th1 and Th2 cells is the type of antigen-presenting cell (APC) involved and its functional characteristics, e.g., the production of interleukin-12. Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE. The potential of cytokines, in particular interleukin-10, and glucocorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed.

Animals↗

PubMed1997

IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice.

IL-10 and IL-4 were studied with respect to their capacity to inhibit experimental allergic encephalomyelitis (EAE) induced in SJL/J mice by immunization with the proteolipid protein peptide PLP139-151. Treatment with 2 micrograms IL-10/day from day 0 until day 12 delayed onset of disease and inhibited the severity of EAE. By contrast, a daily dose of 0.5 microgram IL-4 was ineffective. Instead of acting in a synergistic fashion, IL-4 even abrogated the inhibitory effect of IL-10. The effects of IL-10 and IL-4 treatment were largely consistent with the (lack of) ability of these cytokines to down-regulate the inflammatory response in brain tissue. Although IL-4 was ineffective in the inhibition of EAE, lymph node cells from IL-4-treated mice displayed a strongly inhibited peptide-specific IFN-gamma production. By contrast, IL-10, which was effective in inhibiting EAE, showed no significant inhibition of IFN-gamma at this level. Neither cytokine treatment resulted in detectable levels of peptide-specific IL-4. Indirect evidence for the activity of Th2 cells in vivo came from the observation that IL-10 inhibited the primary PLP139-151-specific IgG2a and IgG3 response in favor of IgG1, whereas IL-4 inhibited the primary antibody response to the peptide, regardless of subclass. The combination of IL-4 and IL-10 did not affect the subclass composition. The observation that IL-10-treated mice remained sensitive to re-induction of EAE is not in support of an important role of Th2 cells in regulating disease activity in this model of actively induced EAE.

Animals↗

PubMed1996

Differences in dexamethasone-sensitivity between lymphocytes from patients with Alzheimer's disease and patients with multi-infarct dementia.

Peripheral blood mononuclear cells (PBMC) from 40 consecutive patients entering a screening program on cognitive impairment were studied in vitro with respect to their sensitivity to dexamethasone (DEX). Phytohemagglutinin-induced proliferation by PBMC from patients with senile dementia of the Alzheimer type (SDAT) was less sensitive to the inhibitory effect of DEX, compared to PBMC from patients with multi-infarct dementia (MID) and PBMC from patients with miscellaneous causes of cognitive impairment (MISC). An intermediate sensitivity was found with PBMC from patients with clinical signs of both MID and SDAT (= MIXED). These differences could not be explained by differences in the composition of the CD4(+) T cell population, interleukin (IL)-2 or IL-4 production, or quantitative differences in the expression of glucocorticoid receptors as measured by flowcytometry. However, the expression of bcl-2 was higher in PBMC from SDAT patients than in cells from MID patients or from MISC patients, whereas the MIXED group showed an intermediate expression; a high bcl-2 expression correlated with a low DEX-sensitivity. These findings suggest that characteristics of PBMC reflect related changes in the central nervous system and indicate that PBMC may be a useful and accessible tool to obtain more insight into the pathogenesis of Alzheimer's disease.

Aged↗

PubMed1996

Correlation between the antibody response to influenza vaccine and helper T cell subsets in healthy aging.

To investigate the effects of the altered composition of the helper T cell compartment in ageing on the humoral response to influenza vaccine, we investigated correlations between helper T cell subsets and anti-influenza antibody responses in 23 JUNIEUR healthy young and 41 SENIEUR healthy elderly subjects. Naive helper T cell numbers (CD4+ CD45RA+) were negatively correlated with antibody production to two of the four strains investigated in JUNIEURS only. By contrast, memory helper T cell numbers (CD4+CD45ROhi) were positively correlated with in vivo IgG antibody titres to three of the four vaccine strains. Age-related differences in the composition of the helper T cell compartment, however, did not explain the lower IgG antibody response that was observed to two of the four vaccine strains examined.

Adult↗