The blood-brain barrier as target of multiple sclerosis research and therapy. Report of an international scientific meeting, Würzburg, January 23/24, 2004.
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Animals↗
Biomedical subjects
Peter Rieckmann
Publications and source records attributed to Peter Rieckmann.
The role of the polio virus receptor and the herpesvirus entry mediator B genes for the development of MS.
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). Although the cause of MS is still uncertain, it is well accepted that both genetic and environmental factors are important for the development of disease. In this study, we focused on the Polio Virus Receptor (PVR) and Herpesvirus entry mediator B (HVEB) receptor genes, which are located on chromosome 19q13, a region previously linked to MS. Both receptors are expressed in the brain and immune system and play an important role for inter-cellular adhesion and entry of neurotropic viruses to the brain. We identified four new polymorphisms in the PVR gene, which were located in the promoter region and three different exons. All exonic polymorphisms altered the amino acid sequence of the receptor. No new polymorphisms were found in the HVEB gene, but we confirmed a previously identified intronic polymorphism. We analyzed the frequency of the polymorphisms by RFLP analysis in sporadic MS patients, MS families, and healthy controls and determined the surface expression of HVEB and PVR on peripheral blood monocytes. We did not find differences in the frequency of the polymorphisms or surface expression between MS patients and controls. Overall, our findings do not support a role of HVEB and PVR genes in the development of MS.
Adult↗
Interferon-beta induces transient systemic IP-10/CXCL10 chemokine release in patients with multiple sclerosis.
Reduction of chemokine expression induced by human recombinant Interferon (IFN)-beta is thought to be a therapeutic mechanism of its action in the treatment of multiple sclerosis (MS). In vitro, IFN-beta can induce chemokine expression. Here we show that a single injection of IFN-beta induced a transient strong increase of IP-10/CXCL10 and a weak elevation of MCP-1/CCL2 plasma levels in MS patients on continuing treatment with IFN-beta. IP-10/CXCL10 bursts, which were not observed in glatiramer acetate (GA)-treated patients, correlated with occurrence of flu-like symptoms. Systemic IP-10/CXCL10 release induced by IFN-beta may influence its therapeutic effect--either negatively or positively.
Adult↗
Cytokine mRNA expression patterns in the disease course of female adolescents with anorexia nervosa.
Anorexia nervosa (AN) is a serious eating disorder characterized by extreme weight loss and abnormalities of the neuroendocrine and immune systems. Cytokines have been discussed to be involved in the pathomechanisms underlying cachexia. Therefore our study aimed at examining the mRNA expression pattern of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood of 11 female AN patients and 10 age and sex matched normal weight control subjects using a sensitive quantitative polymerase chain reaction (PCR) method. We found a significant increase in TNF-alpha and IL-6 mRNA expression in anorectic patients at admission (mean BMI 14.8 +/- 1.3) when compared to controls. During follow-up, the expression of TNF-alpha mRNA remained significantly higher in formerly anorectic patients (mean BMI 18.7 +/- 0.5) while IL-6 mRNA expression decreased. We interpret our results as suggesting that TNF-alpha may contribute to metabolic abnormalities in anorexia nervosa even after goal BMI is achieved.
Acute Disease↗
Health outcomes in multiple sclerosis.
PURPOSE OF REVIEW: Economic considerations are increasingly important in the evaluation of innovative medical technologies. In the past few years, evaluations of cost and cost-effectiveness analysis became a popular topic for multiple sclerosis research. Here, we review cost-of-illness and cost-utility studies in multiple sclerosis published during the past 2 years. RECENT FINDINGS: Despite differences in methodology, several cost-of-illness studies unequivocally demonstrated that indirect costs as a result of sick leave, premature retirement or loss of income made up almost half of the overall costs, and that total costs were higher in the more advanced stages of the disease. Cost-effectiveness studies of recombinant IFN-beta preparations demonstrated a marked variability in the incremental cost per quality-adjusted life-year, with amounts ranging from Euro 28 432 to US$338 738. For glatiramer acetate and mitoxantrone, only limited data are available, but even these few studies differed in their results. SUMMARY: Health outcome studies constitute a new and emerging field of multiple sclerosis research. All studies performed so far underscore the importance of indirect cost in multiple sclerosis. However, the marked differences in cost-effectiveness studies illustrate that the method of economic modeling has considerable impact on the results of these studies, which need standardization in order to evaluate properly the economic consequences of new and expensive therapies in multiple sclerosis.
Cost-Benefit Analysis↗
Downregulation of CXCR1 and CXCR2 expression on human neutrophils by Helicobacter pylori: a new pathomechanism in H. pylori infection?
In Helicobacter pylori gastritis, neutrophil activation and migration, which play central roles in the pathogenesis of the disease, are regulated by the neutrophil attractant chemokines interleukin 8 (IL-8) and Groalpha, whose secretion is induced by H. pylori. However, the modulation of the corresponding chemokine receptors CXCR1 and CXCR2 on human neutrophils under the influence of H. pylori has not been investigated. Incubation of neutrophils with cag(+) and cag deletion H. pylori strains resulted in a complete downregulation of the CXCR1 and the CXCR2 receptors after 0.5 h, as tested by fluorescence-activated cell sorter analysis, independent of the cag status. Downregulation of CXCR1 and CXCR2 seems to occur via receptor internalization and rapid degradation, as shown by confocal microscopy and immunoblotting. Neither the proinflammatory cytokines IL-8 and tumor necrosis factor alpha produced by the neutrophils themselves nor H. pylori lipopolysaccharide, which are the known regulators of these two chemokine receptors, was responsible for the downregulation. Reverse transcription-PCR analysis showed that CXCR1 and CXCR2 mRNAs of neutrophils were reduced at a later time than the CXCR1 and CXCR2 proteins. Moreover, cag(+) H. pylori strains induced significantly stronger downregulation of CXCR1 and CXCR2 mRNAs than the cag deletion mutant. Therefore, receptor protein and mRNA downregulation seem to be mediated by two independent mechanisms. Data obtained by immunohistochemistry suggested that downmodulation of CXCR1 and CXCR2 on neutrophils may also occur in vivo in the human stomach during H. pylori infection. Downregulation of CXCR1 and CXCR2 expression on neutrophils in H. pylori infection by H. pylori itself may represent a new mechanism of modulating neutrophil migration and activation in the gastric mucosa.
Down-Regulation↗
Cytokine mRNA expression in patients with multiple sclerosis and fatigue.
BACKGROUND: Fatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS), but the putative role of proinflammatory cytokines remains to be elucidated. METHODS: Thirty-seven patients (27 women, 10 men) with relapsing remitting (n = 29) and secondary progressive (n = 8) MS, aged 41.0 +/- 10.2 years, were studied. Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for interferon (IFN)-gamma tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured by real time RT PCR. Autonomic function was evaluated by standard tests for parasympathetic and sympathetic function, as well as by serum levels of norepinephrine and epinephrine. RESULTS: Median levels of TNF-alpha mRNA expression were significantly higher in MS patients with (FSS > or = 4.0 and > or = 5.0, n = 26 and n = 14, respectively) than in those without fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression. Cytokine levels were not correlated to autonomic tests or to serum catecholamine levels. CONCLUSIONS: These results suggest that TNF-alpha, as a principal proinflammatory mediator, is associated with MS-related fatigue. This is in support of a pathogenic role of the MS-related inflammatory process in the development of fatigue.
Adult↗
Haematological effects of interferon-beta-1a (Rebif) therapy in multiple sclerosis.
INTRODUCTION: Interferon-beta-1a (Rebif) is an established treatment for relapsing-remitting multiple sclerosis (MS) and haematological changes are commonly reported in clinical trials of this agent. The combined clinical trial and postmarketing safety database for subcutaneous interferon-beta-1a (Rebif) allows a comprehensive, retrospective assessment of both common and infrequent haematological effects associated with interferon-beta therapy. METHODS: Haematological laboratory abnormalities were analysed from six randomised, controlled clinical trials of subcutaneous interferon-beta-1a in MS, five of which were placebo-controlled. Treatment data were collected from 2482 patients for up to 6 months, 1178 patients for up to 2 years and 786 patients for up to 6 years. Total interferon-beta-1a doses ranged from 22 microg once weekly to 44 microg three times weekly. Postmarketing surveillance data were also analysed. RESULTS: Treatment with interferon-beta-1a led to asymptomatic dose-related reductions in all cell lineages under investigation, predominantly white blood cells. The greatest differences between interferon-beta-1a therapy and placebo were seen for total leucocyte and neutrophil counts. At least two-thirds of patients affected by cytopenia experienced the onset of cytopenia within the first 6 months of therapy. The majority of events were mild and generally resolved within 3--4 months, while continuing therapy. Dose reductions were uncommon and only a small proportion (6 of 727; 0.8%) of patients stopped treatment over 2 years because of haematological abnormalities when receiving the highest dose of interferon-beta-1a, 44 microg three times weekly. Postmarketing safety reports were similarly related to asymptomatic cytopenias, although one case of potentially related autoimmune haemolytic anaemia was reported. CONCLUSION: Although haematological abnormalities are common and dose-related in patients with MS receiving interferon-beta-1a, the events are mainly mild and transient, with little impact on adherence to therapy. Haematological events are rarely of clinical significance and do not adversely affect the benefit-to-risk ratio that favours high-dose interferon-beta-1a therapy.
Adjuvants, Immunologic↗
Production of IL-12 and IL-18 in human dendritic cells upon infection by Listeria monocytogenes.
Dendritic cells (DCs) are major antigen-presenting cells of the immune system, which need to be activated in order to initiate an immune response. Here, we describe the immunostimulatory effects on human monocyte-derived DCs observed upon infection with Listeria monocytogenes or after treatment with listerial lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively. All stimuli caused upregulation of costimulatory molecules, induced T-cell proliferative responses and secretion of cytokines in vitro. Infection of DCs with L. monocytogenes induced release of interleukin (IL)-12 and IL-18. In contrast treatment with purified listerial LTA yielded high levels of IL-18 release, but only minimal IL-12 production. Treatment of DCs with LPS conversely induced significant amounts of IL-12 production, but no IL-18. The release of both stimulating cytokines IL-12 and IL-18 upon infection with entire bacteria suggests that attenuated strains of L. monocytogenes may be a valuable tool for subunit vaccine delivery.
Adult↗
A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.
We identified eight patients with a distinct magnetic resonance imaging pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. The uniform, highly characteristic magnetic resonance imaging pattern and the similarities in clinical and magnetic resonance spectroscopy findings provide evidence for a new disease entity. Autosomal recessive inheritance is likely.
Adolescent↗
Influence of VEGF-R2 inhibition on MMP secretion and motility of microvascular human cerebral endothelial cells (HCEC).
Neovascularization and invasion are key features of malignant gliomas. Matrix metalloproteinases (MMPs) are supposed to play a major role mediating these processes. To analyze the expression patterns of MMPs in microvascular human cerebral endothelial cells (HCEC), we isolated endothelial cells from normal human brain microvessels. Characterization of cellular origin was performed by immunostaining, using the endothelial cell markers Ulex europaeus Agglutinin-1, von-Willebrand-Factor and Glucose-transporter-1. Contamination by other cell types was tracked by immunohistochemistry for GFAP (astrocytes), ASM (pericytes) and CD68 (macrophages). Secretion of MMPs was evaluated by ELISA and zymography. To determine whether HCEC show any difference in MMP expression compared to endothelial cells of other origin we analyzed human umbilical vein endothelial cells (HUVEC). HCEC show a decrease of MMP-3 and MMP-2 protein when treated with SU5416, a VEGF-R2 (KDR/flk-1) inhibitor, whereas MMP expression remained unchanged in HUVEC. To determine whether these findings show any effect in the motility of these cells we used a three-dimensional co-culture assay of avascular glioblastoma spheroids with primary HCEC spheroids. Untreated controls showed invasion of both cell populations into each other whereas treatment of the co-cultures with SU5416 resulted in complete inhibition of endothelial cell invasion hence indicating that flk-1 related motility of endothelial cells is critically involved in this process and can be studied with this assay. The results of different effects of anti-angiogenic treatment on proteolytic properties of two endothelial cell populations suggest that neovascularization of human brain tumors in vitro is dependent on the surrounding endothelial cell type and should therefore be studied with organ-specific human microvascular cerebral endothelial cells.
Angiogenesis Inhibitors↗
Building up the blood-brain barrier.
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A Kinase Anchor Proteins↗
Early intervention in multiple sclerosis : better outcomes for patients and society?
Multiple sclerosis (MS) is thought to be a chronic inflammatory disorder of the CNS. The past decade has seen the introduction of the new immunomodulatory drugs, interferon (IFN)-beta and glatiramer acetate, that have considerably improved the therapeutic options for this often disabling disease. The efficacy of these treatments in terms of reducing relapse rate and slowing progression has been proven in several large, multicentre, randomised, controlled trials. Similarly, early IFNbeta treatment of patients with clinically isolated syndromes suggestive of MS has been shown to lengthen time to conversion into definite MS. Cost-effectiveness has been questioned with the increasing use of these innovative and, therefore, costly therapies; however, modern studies with appropriate economic modelling suggest that treatment with IFNbeta may indeed be cost-effective. Since increasing disability is associated with increasing costs, stabilisation of the disease at low functional grades of disability should aim at not only improving quality of life for the individual patient, but provide for prospective cost-benefit analysis focussing on the socioeconomic aspects of MS.
Clinical Trials as Topic↗
Brain derived neurotrophic factor does not act on adult human cerebral endothelial cells.
Brain derived neurotrophic factor (BDNF), known to promote survival of neurons, has recently been involved in the regulation of endothelial cells and was shown to possess immunoregulatory properties. We therefore asked whether BDNF has immunoregulating effects in human cerebral endothelial cells (HCEC). Adult HCEC expressed vascular cell adhesion molecule-1 and HLA class II following stimulation with tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, respectively, but not after BDNF treatment. Addition of BDNF did not modulate the effects of TNF-alpha and IFN-gamma on HCEC, including TNF-alpha induced interleukin-8. Fluorescent activated cell sorting, RT-PCR, and immunohistochemistry indicated that HCEC do not express the trkB or p75 receptors involved in BDNF signaling. These results demonstrate that adult HCEC are not a likely target for BDNF. Novel factors regulating HCEC remain to be identified.
Adult↗
A polymorphism in the human cytotoxic T-lymphocyte antigen 4 ( CTLA4) gene (exon 1 +49) alters T-cell activation.
The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an important modifier of T-cell activation with down-regulatory properties upon B7 engagement. An allelic polymorphism in exon 1 of the CTLA4 gene coding for the peptide leader sequence of CTLA4 was recently described. This polymorphism was detected in association with several autoimmune diseases. In this study, we investigated the functional impact of the CTLA4 exon 1 +49 A/G dimorphism on T-cell activation and cellular localization. We examined the T-cell response from healthy donors either homozygous for A or G at position +49 of the exon 1. Under suboptimal stimulation conditions we found a greater proliferative response of cells from donors homozygous for G at position +49. FACS analysis of CTLA4 expression revealed a reduced up-regulation of CTLA4 from G/G donors upon T-cell activation, if compared with wild-type cells. Intracellular CTLA4 distribution demonstrated qualitatively different staining patterns between the two genotypes as determined using confocal fluorescence microscopy. Our results suggest that the G allele at position +49 of exon 1 affects the CTLA4-driven down-regulation of T-cell activation and may be an important factor in the pathogenesis of autoimmune diseases.
Abatacept↗
Association of a null mutation in the CNTF gene with early onset of multiple sclerosis.
BACKGROUND: Immune-mediated demyelination and axonal damage lead to early functional impairment in multiple sclerosis (MS). Ciliary neurotrophic factor (CNTF) is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. SUBJECTS AND METHODS: We screened 288 unselected patients with multiple sclerosis (MS) (mean age, 40.2 +/- 10.2 years; range, 18-71 years) for a previously described homozygous null mutation within the CNTF gene leading to a truncated, biologically inactive protein. The G-to-A CNTF null mutation at position -6 of the second exon was identified by a HaeIII polymorphism of the polymerase chain reaction-amplified genomic DNA. RESULTS: The homozygous CNTF null mutation (CNTF -/-) was found in 7 (2.4%) of the 288 randomly selected patients with MS. Patients with the CNTF -/- genotype had a significantly earlier onset of disease (17 vs 27 years; Mann-Whitney test, P =.007) with predominant motor symptoms. CONCLUSIONS: These results suggest that CNTF contributes to time and site of early clinical manifestation. The frequency of patients with MS with a homozygous CNTF null mutation in this population was not higher than in control groups, indicating that the CNTF null mutation is not a risk factor for development of MS.
Adult↗
Evidence for shoulder girdle dystonia in selected patients with cervical disc prolapse.
Some patients with cervical disc herniation suffer from persistent nuchal pain and muscle spasms after decompressive surgery despite the lack of clinical and radiological signs for actual spinal root compression. Sonographic examination of the brain in some of these patients showed increased echogenicity of the lentiform nuclei as described in patients with idiopathic dystonia. This has been linked to an altered Menkes protein level and copper metabolism. We suggest a relationship between persistent nuchal pain after adequate cervical disc surgery and dystonic movement disorders. Thirteen patients with persistent nonradicular nuchal pain after at least one cervical disc surgery and without evidence of continuing spinal root compression and 13 age-matched controls were included. All patients had a complete neurological examination, ultrasound, and MRI scan of the brain. In addition, Menkes protein mRNA levels of leucocytes were analyzed in patients and controls. All patients with persistent nuchal pain exhibited a constant tonic unilateral shoulder elevation associated with an ipsilateral hypertrophy of the trapezius muscle. Ultrasound examination showed an increased echogenicity of the lentiform nucleus in one patient unilaterally and in 10 patients bilaterally but in none of the controls. On MRI the T2-values of the lentiform nuclei were found to be higher in patients exhibiting a hyperechogenicity of the lentiform nuclei compared to controls (P = 0.01). In addition, Menkes protein mRNA levels were decreased in patients with cervical disc herniation (P = 0.03). Clinical, neuroimaging, and biochemical findings of this selected patient sample with chronic nuchal pain and muscle spasms after cervical disc surgery resemble alterations in patients with idiopathic cervical dystonia. This suggests a link between both disorders. A peripheral trauma to the nerve roots may precipitate dystonic movements in susceptible patients and chronic dystonic muscle contraction would account for the persistent nuchal pain.
Adenosine Triphosphatases↗
sICAM-1 is not a marker for disease activity in the relapse-free interval of multiple sclerosis--a cross-sectional pilot study.
In multiple sclerosis (MS), serum levels of ICAM-1 were elevated during acute exacerbations and were therefore proposed as a marker of disease activity, but the potential of this molecule as an indicator of long-term activity, i. e. the progression of the disease outside acute exacerbations, is not known. We therefore measured sICAM-1 levels by an enzyme-linked immunosorbent assay in 26 patients with active relapsing-remitting (RR) MS (at least two relapses in the preceding 2 years, but not within the last 30 days), in 10 patients with active secondary-progressive MS (progression of at least one point on the EDSS and/or two relapses in the preceding 2 years, but not within the last 30 days), in 8 patients with stable RR MS (no relapse and no progression during the last two years), and in 16 healthy controls. There was no significant difference between the different MS subtypes and healthy controls, nor within the different MS subtypes. Thus, while sICAM-1 may be useful to indicate short-term activity of MS in terms of relapses and MRI activity, this does not hold true for the long-term activity of MS outside acute exacerbations.
Adult↗