Multiple Sclerosis: Sellebjerg F

Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ, Sellebjerg F, Tourtellotte WW. · Department of Medicine (Neurology), University of Ottawa, Multiple Sclerosis Research Clinic, The Ottawa Hospital, Ottawa, Ontario, Canada. · Arch Neurol. · Pubmed #15956157 links to  free full text

Abstract: New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis. Although rigorous magnetic resonance imaging requirements were provided, the "new criteria paper" fell short in terms of guidelines as to how the CSF analysis should be performed and simply equated the IgG index with isoelectric focusing, without any justification. The spectrum of parameters analyzed and methods for CSF analysis differ worldwide and often yield variable results in terms of sensitivity, specificity, accuracy, and reliability, with no decided "optimal" CSF test for the diagnosis of MS. To address this question specifically, an international panel of experts in MS and CSF diagnostic techniques was convened and the result was this article, representing a consensus of all the participants. These recommendations for establishing a standard for the evaluation of CSF in patients suspected of having MS should greatly complement the new criteria in ensuring that a correct diagnosis of MS is being made.

Hartung HP, Polman C, Bertolotto A, Deisenhammer F, Giovannoni G, Havrdova E, Hemmer B, Hillert J, Kappos L, Kieseier B, Killestein J, Malcus C, Comabella M, Pachner A, Schellekens H, Sellebjerg F, Selmaj K, Sorensen PS. · Dept. of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. · J Neurol. · Pubmed #17457510 No free full text.

Abstract: Interferon beta (IFNbeta) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNbeta sequence, frequency of administration, level of dose and formulation of IFNbeta. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNbeta therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.

Sellebjerg F. · Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. · Dan Med Bull. · Pubmed #16009055 No free full text.

This publication has no abstract.

Sellebjerg F, Sørensen TL. · Department of Neurology, The MS Clinic, University of Copenhagen, Glostrup Hospital, DK-2600 Glostrup, Denmark. · Brain Res Bull. · Pubmed #12909304 No free full text.

Abstract: Chemokines and matrix metalloproteinases (MMPs) play key roles in leukocyte migration across the blood-brain barrier (BBB) in infectious and inflammatory diseases, including multiple sclerosis (MS). In MS some chemokine receptors are expressed by an increased percentage of T cells in blood, the CSF concentration of chemokine ligands for these receptors is increased, and there is accumulation of T cells expressing relevant chemokine receptors in CSF and in the CNS parenchyma. Chemokine receptor expression patterns appear to reflect disease activity and disease stage in MS. MMPs are constitutively expressed or induced by proinflammatory cytokines and chemokines in leukocytes and CNS-resident cells. Several MMPs are expressed in MS plaques, and the CSF concentration of MMP-9 is increased in MS. The CSF concentration of MMP-9 may reflect disease activity in MS, and the CSF concentration of MMP-9 is higher in patients carrying the MS-associated HLA type DRB1 1501. We review how chemokines and MMP-9 may be involved in the pathogenesis of MS by controlling leukocyte migration between different functional compartments. Measuring expression of these molecules may find use as surrogate markers of disease activity in MS, and interfering with their function holds promise as a novel therapeutic strategy in MS.

Sellebjerg F, Barnes D, Filippini G, Midgard R, Montalban X, Rieckmann P, Selmaj K, Visser LH, Sørensen PS, Anonymous00318. · Danish MS Centre, Copenhagen University Hospital, Denmark. · Eur J Neurol. · Pubmed #16324087 No free full text.

Abstract: Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

Sellebjerg F, Datta P, Larsen J, Rieneck K, Alsing I, Oturai A, Svejgaard A, Soelberg Sørensen P, Ryder LP. · Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Mult Scler. · Pubmed #18408020 No free full text.

Abstract: Treatment with interferon-beta (IFN-beta) induces the expression of hundreds of genes in blood mononuclear cells, and the expression of several genes has been proposed as a marker of the effect of treatment with IFN-beta. However, to date no molecules have been identified that are stably induced by treatment with IFN-beta. We use DNA microarrays to study gene expression in 10 multiple sclerosis (MS) patients who began de novo treatment with IFN-beta. After the first injection of IFN-beta, the expression of 74 out of 3428 genes changed at least two-fold and statistically significantly (after Bonferroni correction). In contrast, we observed no persisting effects of IFN-beta on gene expression. Among the most strongly induced genes was MXA, which has been used in previous biomarker studies in MS. In addition, the study identified the induction of LGALS9 and TCIR1G, involved in negative regulation of T helper type I immunity and T-cell activation, as novel effects of IFN-beta therapy in MS.

Sellebjerg F, Ross C, Koch-Henriksen N, Sørensen PS, Frederiksen JL, Bendtzen K, Sørensen TL. · The MS Clinic, Copenhagen University Hospital, Glostrup, Denmark. · Mult Scler. · Pubmed #16320722 No free full text.

Abstract: Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta.

Lim ET, Sellebjerg F, Jensen CV, Altmann DR, Grant D, Keir G, Thompson EJ, Giovannoni G. · Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. · Mult Scler. · Pubmed #16193890 No free full text.

Abstract: The objectives of this study were (1) to determine how cerebrospinal fluid (CSF) neurofilament heavy chain (NfH(SM134) and NfH(SM135)) levels relate to clinical outcome in optic neuritis (ON) and multiple sclerosis (MS) relapse patients treated with high dose oral methylprednisolone; and (2) to correlate neurofilament and myelin basic protein (MBP) concentrations, particularly as the latter was previously associated with clinical disability. Fifty subjects participated in two double-blind, randomized, placebo-controlled clinical trials. Eight/18 patients in the ON trial and 15/32 subjects in the MS attack trial were treated with oral methylprednisolone. In the MS attack trial group, CSF NfH(SM134) and NfH(SM135) measured at week 3 and deltaCSF NfH(SMI34) levels from baseline to week 3 were predictive of clinical outcome at week 8 and 52. In the ON group, no such association was seen. When both groups were combined, baseline CSF NfH(SHM134) and NfH(SM135) correlated positively with baseline enhancing lesion volume (ELV) (r(s) =0.50, P <0.01 and rS =0.53, P <0.01, respectively). Levels of NfH(SM135) at baseline and week 3 also strongly correlated with the MBP concentration. This study supports the view that acute inflammation in ON and MS results in axonal pathology and that the latter has a role in determining functional impairment.

Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M, Anonymous00090. · MS Research Unit, Department of Neurology 2082, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark. · Neurology. · Pubmed #15596745 No free full text.

Abstract: OBJECTIVE: To investigate if IV immunoglobulins (IVIg) in combination with methylprednisolone make recovery from a relapse faster and more complete than methylprednisolone alone. Design/ METHODS: The authors studied 76 patients with multiple sclerosis (MS) who had an acute relapse with involvement of visual function, upper limb motor function, or gait, and with onset of symptoms between 24 hours and 14 days before. Patients were treated with either IVIg 1 g/kg or placebo (0.1% human albumin), given 24 hours before treatment with IV methylprednisolone 1 g on 3 consecutive days. RESULTS: Both groups improved, but the authors observed no significant difference between IVIg and placebo patients regarding the primary endpoint, the mean change in the Z-score of the individually chosen targeted neurologic deficit (the most affected system) from baseline to 12 weeks (p = 0.89). A slightly better, but not significant remission was seen in the IVIg group in global scores, i.e., Expanded Disability Status Scale (p = 0.23) and Multiple Sclerosis Impairment Scale (p = 0.24), and in time to next relapse (p = 0.22). CONCLUSIONS: The results do not justify routine application of IV immunoglobulins as add-on therapy to IV methylprednisolone in the treatment of acute multiple sclerosis attacks.

Sellebjerg F, Jensen CV, Larsson HB, Frederiksen JL. · The MS Clinic, Department of Neurology, University of Copenhagen, Glostrup Hospital, DK-2600 Glostrup, Denmark. · Mult Scler. · Pubmed #12617276 No free full text.

Abstract: Oral high-dose methylprednisolone treatment is efficacious in acute optic neuritis (ON) and attacks of multiple sclerosis (MS). The responses to treatment in subgroups of patients participating in two randomized, controlled trials were assessed. Fifty-eight patients with ON and 51 patients with attacks of MS were treated with placebo or oral methylprednisolone (500 mg daily for five days with a 10-day tapering period). A gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) scan was obtained at baseline in 66 patients, and 29 patients underwent repeated MRI studies. Seventy-four patients underwent lumbar puncture before treatment. The odds ratio (OR) of improvement after methylprednisolone treatment (a one point change in the visual function system score of the Kurtzke Expanded Disability Status Scale (EDSS) in ON or in the EDSS score in attacks of MS) was higher in patients with enhancing lesions on baseline MRI (one week: OR 15, P = 0.02; eight weeks: OR 4.6, P = 0.02). Methylprednisolone treatment suppressed Gd-enhancement after one week (P < 0.001) and three weeks (P = 0.001). Cerebrospinal fluid measures of intrathecal inflammation correlated with the area of Gd-enhancement but did not correlate as closely with the treatment response as did the results of Gd-enhanced MRI. These findings suggest that the resolution of intrathecal inflammation as assessed by Gd-enhanced MRI is a major effect of oral high-dose methylprednisolone.

Sellebjerg F, Giovannoni G, Hand A, Madsen HO, Jensen CV, Garred P. · Department of Neurology, University of Copenhagen, Glostrup Hospital, Nordre Ringvej 57, DK-2600 Glostrup Copenhagen, Denmark. · J Neuroimmunol. · Pubmed #11960657 No free full text.

Abstract: The role of nitric oxide (NO) in multiple sclerosis (MS) is not clear. We found increased cerebrospinal fluid concentrations of the NO degradation products nitrate (NO(x)) in clinically definite MS but not in clinically isolated syndromes. High CSF concentrations of NO(x) correlated with long attack duration. Patients carrying the truncated CC chemokine receptor allele CCR5 Delta32 had lower serum concentration of NO(x) at later attack stages. NO(x) concentrations did not change after methylprednisolone treatment but high concentrations were associated with more pronounced treatment responses. These findings suggest an association of high CSF levels of NO(x) with more severe disease activity in relapsing-remitting MS.

Sørensen TL, Sellebjerg F, Jensen CV, Strieter RM, Ransohoff RM. · The MS Clinic, Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup Copenhagen, Denmark. · Eur J Neurol. · Pubmed #11784351 No free full text.

Abstract: Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS patients in relapse, whilst levels of CCL2 (MCP-1) were reduced. Here, we report a serial analysis of CSF CXCL10 and CCL2 concentrations in 22 patients with attacks of MS or acute optic neuritis (ON) treated with methylprednisolone, and 26 patients treated with placebo in two randomized controlled trials. Chemokine concentrations were measured by enzyme linked immunosorbent assay (ELISA) in CSF obtained at baseline and after 3 weeks, and were compared with other measures of intrathecal inflammation. At baseline CSF concentrations of CCL2 were significantly lower in the patient group than in controls. The levels of CXCL10 were higher in the patient group than in controls but two outliers in the control group also had high CSF concentrations of CXCL10. The CSF concentrations of CXCL10 did not change over time or after treatment. The CSF concentration of CXCL10 was positively correlated with the CSF leukocyte count, the CSF concentration of neopterin, matrix metalloproteinase (MMP)-9, and intrathecal IgG and IgM synthesis. The concentration of CCL2 increased between baseline for 3 weeks in both groups, more distinctly so in patients treated with methylprednisolone. CCL2 correlated negatively with MMP-9 and IgG synthesis levels. CXCL10 may be involved in the maintenance of intrathecal inflammation whereas CCL2 correlates negatively with measures of inflammation, suggesting differential involvement of CXCL10 and CCL2 in CNS inflammation.

Sørensen TL, Roed H, Sellebjerg F. · The MS Clinic, Department of Neurology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark. · J Neuroimmunol. · Pubmed #11777551 No free full text.

Abstract: We investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of multiple sclerosis (MS) and in neurological controls. Chemokine receptor expression was also studied in interferon-beta-treated patients with relapsing-remitting or secondary progressive MS. We observed significantly higher expression of CXCR3 on B cells in the CSF in active MS than in controls. Patients with active MS also had higher B-cell expression of CCR5 in blood. No major differences between RRMS and SPMS patients were detected, and chemokine receptor expression was not affected by interferon-beta treatment.

Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. · Neurologisk afdeling, Amtssygehuset i Glostrup. · Ugeskr Laeger. · Pubmed #10643347 No free full text.

Abstract: The efficacy of glucocorticoid treatment in multiple sclerosis (MS) is uncertain. We assessed the effect of oral high-dose methylprednisolone in attacks of MS. Twenty-five patients with an attack of MS with a duration of less than four weeks were randomized to placebo, 26 patients received oral methylprednisolone (500 mg once daily for five days with a 10 days tapering period). Scripps Neurological rating scale scores differed significantly in methylprednisolone and placebo-treated patients the first three weeks (p = 0.005) and after eight weeks (p = 0.0007). Subjective symptom assessment on a visual analogue scale the first three weeks (p = 0.02) and the answers to an efficacy questionnaire administered after eight weeks (p = 0.05) also favoured a beneficial effect of methylprednisolone treatment. The risk of a new attack of MS was not influenced by the treatment at short-term follow up. No serious adverse events were seen. Oral high-dose methylprednisolone is recommended for treatment of attacks of MS.

Oturai AB, Koch-Henriksen N, Petersen T, Jensen PE, Sellebjerg F, Sorensen PS. · The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen. · Eur J Neurol. · Pubmed #19364368 No free full text.

Abstract: INTRODUCTION: Previous studies of natalizumab (Tysabri) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity. PATIENTS AND METHODS: We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy. RESULTS: During a median observation time of 11.3 months (range 3.0-21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with >or=2 relapses or sustained increase in EDSS of >or=2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab. CONCLUSIONS: Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.

Khademi M, Bornsen L, Rafatnia F, Andersson M, Brundin L, Piehl F, Sellebjerg F, Olsson T. · Neuroimmunology Unit, CMM, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. · Eur J Neurol. · Pubmed #19220425 No free full text.

Abstract: BACKGROUND: Natalizumab affects systemic cytokine expressions and clinical course in relapsing-remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. METHODS: mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. RESULTS: Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-gamma and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. CONCLUSIONS: Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy.

Hesse D, Frederiksen JL, Koch-Henriksen N, Schreiber K, Stenager E, Heltberg A, Ravnborg M, Bendtzen K, Sellebjerg F, Sorensen PS. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Denmark. · Eur J Neurol. · Pubmed #19087149 No free full text.

Abstract: Background and purpose: Neutralizing antibodies (NAbs) appearing during treatment with Interferon-beta (IFN-beta) reduce or abolish bioactivity and therapeutic efficacy. Initial combination therapy with methylprednisolone (MP) may reduce the frequency of NAb positive patients. We hypothesized that MP treatment might also reduce NAb levels and re-establish IFN-beta bioactivity in patients already NAb+, who discontinue IFN-beta therapy. Methods: In a 6-month open-label trial, we compared monthly high-dose pulsed MP treatment in 38 Nab positive patients with 35 NAb+, MP-untreated control patients discontinuing any therapy or switching to glatiramer acetate. All patients were NAb+ with an absent in vivo response to IFN-beta. NAbs were measured using a cytopathic effect assay and expressed as neutralizing capacity (NC) in percentage of added IFN-beta. Bioactivity was expressed as in vivo Myxovirus Resistance Protein A (MxA) mRNA induction in whole blood using real time PCR. Results: At the end of study, median NAb NC was 92% in both groups. Eight patients (21%) in the MP group and four patients (11%) in the control group had regained an in vivo MxA response to IFN-beta (P = 0.35). Conclusions: Monthly pulsed MP treatment in NAb positive patients has no beneficial effect on NAb status or IFN-beta bioactivity.

Sorensen PS, Sellebjerg F. · Danish Multiple Sclerosis Research Center, Department of Neurology, Rigshospitalet, DK-2100, Copenhagen, Denmark. · Lancet. · Pubmed #18970966 No free full text.

This publication has no abstract.

Hedegaard CJ, Krakauer M, Bendtzen K, Sørensen PS, Sellebjerg F, Nielsen CH. · Institute for Inflammation Research, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. · Clin Immunol. · Pubmed #18653385 No free full text.

Abstract: Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p<0.007-0.03), while the IL-6 production increased (p<0.03). No significant change was observed in the MBP-induced CD4+ T cell proliferation, or in the production of IL-4, IL-5 and brain-derived neurotrophic factor. In comparison, IFN-beta therapy reduced IFN-gamma and IL-4 responses to TT (p<0.003 and p<0.04). Thus, IFN-beta inhibits IFN-gamma production in general, presumably alleviating the detrimental influence of IFN-gamma in MS. However, the increase in proinflammatory IL-6 and the decrease in anti-inflammatory IL-10 responses suggest that IFN-beta has more diverse effects than previously assumed.

Sørensen PS, Sellebjerg F. · Rigshospitalet, Dansk Multipel Sclerose Center, Neurologisk Afdeling 2082, København Ø. · Ugeskr Laeger. · Pubmed #18565303 No free full text.

Abstract: In 1996 interferon (IFN)beta was the first biopharmaceutical product to be approved for the treatment of relapsing-remitting multiple sclerosis (MS). In 2006 the more potent monoclonal antibody natalizumab was approved. Presently, a number of monoclonal antibodies are being studied, including alemtuzumab, daclizumab and rituximab, which have all shown promising results. However, the monoclonal antibodies generally have a less favourable safety profile and are more expensive than the currently used first-line therapies, IFNb and glatiramer acetate.

Krakauer M, Sorensen P, Khademi M, Olsson T, Sellebjerg F. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet Copenhagen, Denmark. · Mult Scler. · Pubmed #18424480 No free full text.

Abstract: BACKGROUND: Interferon (IFN)-beta therapy in multiple sclerosis (MS) has been suggested to promote a deviation from T lymphocyte production of pathogenic Th1 cytokines to less detrimental Th2 cytokines, but this is still controversial. We studied patterns of in vivo blood mononuclear cell (MNC) and whole blood cytokine and transcription factor mRNA expression before and during IFN-beta therapy in MS. METHODS: Twenty patients with relapsing-remitting MS were sampled before and after 3 months of treatment with IFN-beta along with 15 healthy volunteers. An additional 39 patients and 50 healthy volunteers served to confirm initial findings. mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR). RESULTS: We found elevated expression of interleukin (IL)-23 and IL-10 in untreated MS patients. IFN-beta therapy increased IL-10 and decreased IL-23 expression independently of any Th1 or Th2 cytokines. The largest changes in cytokine mRNA levels occurred early (~9-12 h) after an IFN-beta injection. CONCLUSION: We found no evidence of a Th1- or Th2-mRNA-promoting effect of IFN-beta therapy. The therapeutic effect of IFN-beta is more likely attributable to the induction of the regulatory cytokine IL-10. The elevated IL-23 mRNA levels in MS patients are noteworthy in view of the newly discovered IL-23-driven Th17 T-cell subset, which is crucial in animal models of MS. Since IFN-beta therapy resulted in decreased IL-23 mRNA levels, the Th17 axis could be another target of IFN-beta therapy.

Sellebjerg F, Oturai A, Sørensen PS, Anonymous00385. · Dansk Multipel Sclerose Center, Neurologisk Klinik 2082, Rigshospitalet, DK-2100 København Ø. · Ugeskr Laeger. · Pubmed #18397664 No free full text.

This publication has no abstract.

Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH. · Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Immunology. · Pubmed #18397264 No free full text.

Abstract: Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-gamma and TNF-alpha, and lower amounts of IL-10, than cells from healthy controls (P<0.03 to P<0.04). Five patients with MS and no controls, displayed MBP-induced CD4+ T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-gamma, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P<0.002 to P<0.01). A strong correlation was found between the MBP-induced CD4+ T-cell proliferation and production of IL-17, IFN-gamma, IL-5 and IL-4 (P<0.0001 to P<0.01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P=0.04 and P=0.007). These data suggest that autoantigen-driven CD4+ T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.

Sellebjerg F, Kristiansen TB, Wittenhagen P, Garred P, Eugen-Olsen J, Frederiksen JL, Sørensen TL. · The MS Clinic, Department of Neurology, Glostrup Hospital, University of Copenhagen, 57 Nordre Ringvej, DK-2600 Glostrup, Denmark. · Acta Neurol Scand. · Pubmed #17511851 No free full text.

Abstract: OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were analyzed in 109 patients with relapsing-remitting MS treated with IFN-beta who were followed clinically for 1 year. Cellular CCR5 expression was measured by flow cytometry. RESULTS: Patients with MS had a higher percentage of CCR5-positive monocytes than healthy controls. Increased monocyte expression of CCR5 correlated weakly with an increased short-term relapse risk but there was no relationship between CCR5 Delta32 allele and CCR5 promoter polymorphism genotypes and relapse risk. CONCLUSIONS: The results do not support a major role of CCR5 in the pathogenesis of relapses in MS patients treated with IFN-beta, but it is possible that monocyte CCR5 expression may be used as a marker of disease activity.

Stoevring B, Jaliashvili I, Thougaard AV, Ensinger C, Høgdall CK, Rasmussen LS, Sellebjerg F, Christiansen M. · Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark. · Scand J Clin Lab Invest. · Pubmed #17101549 No free full text.

Abstract: OBJECTIVE: Tetranectin (TN) is a glycoprotein and C-type lectin thought to play a prominent role in tissue remodelling. The aim of this study was to determine the TN serum and cerebrospinal fluid (CSF) concentration in patients with multiple sclerosis (MS) and controls. MATERIAL AND METHODS: Two-hundred-and-four patients, divided into four diagnostic groups, i.e. definite MS (n = 76), possible onset symptoms of MS (n = 48), other non-inflammatory neurological diseases (n = 61) and other inflammatory neurological diseases (n = 19) and 47 controls with no history of neurological disease were analysed for TN in serum and CSF using a polyclonal sandwich ELISA. RESULTS: All tested groups, e.g. definite MS, possible onset symptoms of MS, other neurological disease, both inflammatory and non-inflammatory, had decreased concentrations of TN in the CSF compared to the concentrations in controls. The quotient of TN in CSF divided by the concentration in serum (QTN) correlated significantly with the same quotient of albumin (QALB), was significantly correlated with the same quotient of albumin QALB. To account for differences in blood brain barrier permeability, we calculated a TN-index defined as: TN-index = QTN/QALB. QTN was significantly decreased in all groups compared to that in controls. However, in definite MS and patients with first attack of MS, the TN-index was not significantly different from that of controls. In contrast, other neurological diseases, both inflammatory and non-inflammatory, were associated with a decreased TN-index. CONCLUSION: These results indicate that TN may play a role in neurological diseases and may serve as a diagnostic aid in MS.