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PubMed2005

Defining the response to multiple sclerosis treatment: the role of conventional magnetic resonance imaging.

During the last two decades, conventional MRI (cMRI) has been extensively used in the diagnostic workup of multiple sclerosis (MS) patients, to monitor the natural history of the disease and to evaluate the efficacy of experimental treatments in randomised, controlled clinical trials. In the latter context, a major issue is represented by the high intra- and inter-individual heterogeneity of the MS patterns of disease activity and evolution. Such heterogeneity might explain, at least partially, the weak correlations found between clinical and cMRI aspects in patients with established MS, which is particularly evident when individual patients are considered. As a consequence, the definition of response to MS treatment, when based upon cMRI aspects, is still a challenging task. Although the use of cMRI-derived quantities as a standalone approach to define treatment options and strategies at an individual patient level should be discouraged, an evidence-based integration of clinical and cMRI data might be helpful in selected cases for an optimal work-up of patients undergoing immunomodulating or immunosuppressive treatments.

Evidence-Based Medicine↗
PubMed2006

COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). IL-12 plays a crucial role in the pathogenesis of EAE/MS and inhibition of IL-12 production or IL-12 signaling was effective in preventing EAE. Cyclooxygenase (COX-2) is a key enzyme promoting inflammation in rheumatoid arthritis and tumor induced angiogenesis. Recent studies have shown that COX-2 inhibitors prevent EAE, however, their mechanism of action is not fully understood. In this study, we show that in vivo treatment (i.p.) with 100 mug COX-2 selective inhibitors (LM01, LM08, LM11, and NS398), on every other day from day 0 to 30, significantly reduced the incidence and severity of EAE in SJL/J and C57BL/6 mice. Further analyses showed that the COX-2 inhibitors reduced neural antigen-induced IL-12 production, T cell proliferation and Th1 differentiation ex vivo and in vitro. The COX-2 inhibitors also decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate that COX-2 inhibitors ameliorate EAE in association with the modulation of IL-12 signaling through JAK-STAT pathway leading to Th1 differentiation and suggest their use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.

Animals↗
PubMed2004

Differential cerebellar activation on functional magnetic resonance imaging during working memory performance in persons with multiple sclerosis.

OBJECTIVE: To explore the potential role of the cerebellum in working memory dysfunction in multiple sclerosis (MS). DESIGN: Blood oxygen level dependent functional magnetic resonance imaging (fMRI) was used to examine cerebellar activation during a working memory task. SETTING: University-affiliated medical rehabilitation facility. PARTICIPANTS: Eight persons with MS and 5 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in hemodynamic response. fMRI data were acquired and subsequently analyzed by using Statistical Parametric Mapping. RESULTS: Both the control and MS groups showed significantly greater activations in the right cerebellar hemisphere as compared with the left side. Persons with MS, however, showed no detectable activations in 4 cerebellar substructures that were significantly active in controls (ie, right vermis, right dentate nucleus, right tonsil, cerebellar peduncle). CONCLUSIONS: The significantly decreased cerebellar activation in the MS group suggests that the cerebellum may play a role in the working memory impairment observed in MS.

Adolescent↗
PubMed2006

Western and Asian features of multiple sclerosis in Mexican Mestizos.

OBJECTIVES: The objective of this study was to compare the clinical expression of MS in Mexican Mestizos with that of patients of European or Asian descent; as well as to compare the annual frequency of new cases with that observed in the previous decades. PATIENTS AND METHODS: All patients with diagnosis of definite MS seen at the National Institute of Neurology and Neurosurgery of Mexico from January 1993 to December 2003 were studied (n=312). Sociodemographic and clinical characteristics were compared with reports of patients from either Western or Asian origin; the long-term disability score was analyzed according to gender, age of onset of MS and the initial symptom. RESULTS: The clinical expression of MS in Mexican Mestizos shares some characteristics with both, Asian and Western forms of MS indicating that the genetic composition of Mexican Mestizos participates in the clinical expression of the disease. Also, at the prevalence date, the mean age of patients and the duration of the disease were lower in our patients than in MS patients from endemic countries suggesting a true increasing incidence in recent times, rather than only improved case ascertainment. CONCLUSIONS: Clinical expression of MS in Mexican Mestizos shows the coexistence of some features common in European and in Asian cases.

Adult↗
PubMed2004

Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis.

MSRV is a retroviral element previously isolated in cell cultures from patients with multiple sclerosis. It is part of a new multi-copy endogenous retrovirus family named HERV-W and displays pro-inflammatory properties both in vitro in human PBMC cultures and in vivo in a humanized SCID mice model. In the present study, we have evaluated potential links between the pro-inflammatory properties of MSRV envelope protein and MS disease. Thus, cytokine productions mediated by the surface unit of MSRV envelope protein were evaluated in PBMC of MS patients and compared with healthy controls. Divergent reactivity to ENV-SU between MS and control PBMC was observed and was reflected by a significant increase of IFN-gamma, IL-6 and IL-12p40 production by the tested MS population. Interestingly, the overproduction of IL-6 and IL-12p40 was found to correlate with disease severity (EDSS) in most patients. Altogether our data suggest that MSRV envelope protein may induce an abnormal cytokine secretion, thus contributing to the inflammatory process in MS.

Adult↗
PubMed2001

Pupillary disturbances in multiple sclerosis: correlation with MRI findings.

UNLABELLED: Autonomic nervous system disturbances such as pupillary abnormalities have rarely been evaluated in multiple sclerosis (MS). However, pupillary impairment is not uncommon in MS and its origin is still unclear. The aim of this study was to investigate pupillary disturbances in MS and to try to correlate pupillary defects with spinal cord and brainstem magnetic resonance imaging (MRI) findings. We prospectively studied 45 MS patients and 30 normal subjects. METHODS: The pupillary contraction latency and the amplitude of contraction were recorded by pupillometry. We also determined afferent and efferent pathway defects by comparing the direct and consensual pupillary reflexes. We evaluated brainstem and spinal cord demyelinating lesions and spinal cord cross-sectional area on MRI. At least one pupillometric parameters were significantly impaired in 60% of patients and in none of the controls. We did not find any correlation between pupillary defect and demyelinating lesions on MRI. The most frequent abnormality was efferent pathway shift and this was correlated with spinal cord atrophy (P<0.02). These results confirm that the autonomic nervous system, and especially pupillary function, is frequently impaired in MS. The parasympathetic system is most commonly affected and this is most likely linked to axonal loss (demonstrated by spinal cord atrophy) rather than to demyelinating lesions.

Adult↗
PubMed1999

CD80 (B7-1) and CD86 (B7-2) expression in multiple sclerosis patients: clinical subtype specific variation in peripheral monocytes and B cells and lack of modulation by high dose methylprednisolone.

Autoimmune activation of T cells by central nervous system (CNS)-derived antigens is hypothesised to underlie neural damage in multiple sclerosis (MS) patients. The role of coreceptor mediated signalling is currently under investigation in order to further elucidate the immunopathogenic mechanisms implicated and to determine possible targets for immune modulation. We have investigated whether differential coreceptor (B7-1/CD80; B7-2/CD86; CD28) expression on circulating lymphocytes and monocytes is (i) a feature of distinctive clinical subtypes of MS (relapsing-remitting in remission/stable-RRMS; relapsing-remitting in relapse/relapsing-RRMS; primary progressive/PPMS), (ii) related to disease activity, and (iii) altered by high dose corticocosteroid treatment. CD80(+) B cells were significantly reduced (P<0.05) in PPMS (4.0+/-0.8%) compared with normal subjects (CON) (9.1+/-1.1%), stable-RRMS (6.7+/-0.7%) and relapsing-RRMS (7.8+/-0.9%) patients. Comparatively fewer monocytes from relapsing-RRMS patients expressed CD86 (relapsing-RRMS 50+/-4.9% vs. stable-RRMS 75.1+/-3.4%, PPMS 77. 7+/-3.2%, CON 72.1+/-3.6%/P<0.05). Otherwise expression of coreceptors did not vary significantly between the groups. A 3-day course of methylprednisolone therapy did not alter coreceptor expression, but did suppress monocyte and B cell HLA-DR expression. There is evidence for differential coreceptor expression on circulating B cells and monocytes in MS disease subtypes. The biological significance of these findings is discussed in relation to alternative theories regarding coreceptor functioning.

Antigens, CD↗
PubMed2006

[From psychometry to neuropsychological disability in multiple sclerosis: a new brief French cognitive screening battery and cognitive risk factors].

INTRODUCTION: Cognitive deficit in multiple sclerosis (MS) is a frequent early feature in the disease course, which conditions patients' overall disability. The goals of this study were to validate a reproducible brief screening battery written in French and to examine cognitive risk profiles in patients with a mild physical disability. METHODS: Cognitive performances of 40 patients with EDSS <4.5 were compared with those of a control group. The study was completed with an analysis of socio-demographic, clinical and psychological variables (questionnaires). RESULTS: Three tests were discriminative with satisfactory predictive values (positive: 88 percent; negative: 96 percent) and a time duration <30 minutes: PASAT (hard condition), backward digit span, learning stage of California Verbal Learning Test. Four variables were associated with cognitive deficit: educational level <11 years, age >40 years, pathological laughing-crying, unemployment. CONCLUSIONS: Our brief battery is an easy and reproducible tool. Completed with warning signs indicating the need for neuropsychological screening, this tool provides the practitioner with a global means of assessing disease activity and potentially therapeutic efficacy.

Adult↗
PubMed2001

Glatiramer acetate and IFN-beta act on dendritic cells in multiple sclerosis.

Glatiramer acetate (GA; Copolymer 1; Copaxone) and interferon-beta (IFN-beta) modulate the course of multiple sclerosis (MS), but probably by different mechanisms. GA, a mixture of synthetic peptides, is believed to act as an altered peptide ligand with inhibitory effects on autoreactive T cells and promoting Th2 cells. It is unknown whether GA affects dendritic cells (DCs), which, besides strong antigen presenting capacity, orchestrate Th1 and Th2 responses. IFN-beta inhibits IL-12 production by DCs over unknown mechanisms. This study was designed to investigate in vitro effects of GA and IFN-beta on the development and function of DCs from MS patients and healthy controls, and to explore their possible synergistic effects on DCs. DCs were generated from adherent blood mononuclear cells (MNCs). GA or IFN-beta or both, when added at initiation of DC cultures, rapidly promoted the development of adherent MNCs into floating, activated DCs as reflected by up-regulation of HLA-DR and CD86 expression. IFN-beta, but not GA, induced IL-3R expression on DCs. Compared to DCs from healthy controls, MS patients' DCs expressed higher levels of the myeloid DC marker CD1a and produced lower amounts of IL-10. GA reduced IL-12 production by DCs. IFN-beta also reduced IL-12, but increased IL-10 production by DCs from both MS patients and healthy controls. GA and IFN-beta synergistically suppressed CD1a and enhanced CD86 expression on MS DCs. These findings document novel mechanisms of action of GA and IFN-beta at the DC level in MS.

Adjuvants, Immunologic↗
PubMed2001

IL-7-enhanced T-cell response to myelin proteins in multiple sclerosis.

In this study, we investigated the in vitro proliferative response of peripheral blood T lymphocytes from MS patients and controls to MBP and MOG either in the absence or in the presence of the conditioning factor IL-7. In the absence of IL-7, T-cell reactivity to MOG and MBP was similar in MS patients and controls even if an increased MBP response was found in a subgroup of patients with active disease. In the presence of IL-7, increased T-cell reactivity to MBP was observed in MS patients suggesting that their MBP-specific T cells are in a different functional state.

Adult↗
PubMed2002

Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-kappa B.

The protective role of pregnancy in autoimmune conditions, such as multiple sclerosis (MS), is potentially associated with immune regulation by sex hormones produced during pregnancy. This study was undertaken to examine the regulatory effects of estriol on the T cell functions, including transmigration and the cytokine production. The results revealed for the first time that estriol significantly inhibited T cell transmigration at a concentration range typical of pregnancy, which correlated with decreased T cell expression of matrix metalloproteinase-9. Estriol was also found to alter the cytokine profile of T cells toward Th2 phenotype by up-regulating the production of IL-10 and inhibiting TNFalpha secretion of T cells. However, the inhibitory effects of estriol on T cells were not antigen-dependent. Further characterization indicated that estriol inhibited nuclear transcription factor kappa B (NF-kappa B), which controls a variety of immune-related genes. This study provides new evidence that estriol is a potent regulator for the T cell functions potentially through its interaction with the NF-kappa B signaling pathway.

Adult↗
PubMed2003

Cytokine producing CD8+ T cells are correlated to MRI features of tissue destruction in MS.

Specific T-cell subsets and their ability to produce cytokines have been involved in concepts of multiple sclerosis (MS) pathogenesis. Evidence to link cytokine producing T-cell subsets to magnetic resonance imaging (MRI) features of tissue destruction, however, is limited. Cytokine flow cytometry was performed in 124 patients with different subtypes of MS. In a subgroup of 69 patients, from whom longitudinal MRI was available, the ability of circulating types 1 and 2 helper T cells to produce cytokines was correlated to changes in T1 hypointense and T2 hyperintense lesion load (LL) on brain MRI during 3 years of follow-up. Significant negative correlations were found between baseline CD8(+) T-cell subsets producing IL-2, IL-4 or IL-13 and the change in T1 LL. Subgroup analyses demonstrated that in RRMS, CD8(+) T cells producing IL-2, IL-4 or IL-13, and in PPMS, CD8(+) IL-10(+) T cells correlated negatively with T1 LL. To our knowledge, this study provides the first direct immunophenotypic evidence of cytokine producing CD8(+) T cells being directly related to long-term development of MRI features of demyelination and axonal loss.

Analysis of Variance↗
PubMed2000

Analysis of effector CD4 (OX-40+) and CD8 (CD45RA+CD27-) T lymphocytes in active multiple sclerosis.

OBJECTIVE: Recently, effector T-cell subpopulations have been identified that can be distinguished by expression of members of the TNF-R family: CD4+OX-40+ cells are CD4 helper-effector cells CD8+CD45RA+CD27 cells are CD8-killer-effector cells. We investigated whether these lymphocyte subsets were increased in the active phase of multiple sclerosis (MS). MATERIAL AND METHODS: Multiple colour immunofluorescence staining was performed on peripheral blood lymphocytes of 28 patients with active MS and of 29 healthy controls, followed by FACS analysis. RESULTS: Frequencies of CD8-killer-effector cells showed a wide interindividual range in both groups and percentages of CD4 helper-effector cells were low. No significant difference between the groups was observed for these subsets, but CD8+CD45RA-CD27 were increased in MS. In healthy individuals, CD4 helper-effector cells correlated with the total percentages of memory cells. Moreover, CD4+ and CD8 memory cells were strongly correlated. CONCLUSION: The here described recently identified effector CD4 and CD8 lymphocyte subpopulations were not increased in clinically active MS. It is however still possible that in MS, myelin-specific encephalitogenic cells reside within these subsets.

Adult↗
PubMed2001

Measurement of intracellular cytokines in MS patients treated with beta-interferon and association of a beta-interferon induced exacerbation with increased expression of gamma-interferon by monocytes.

The effects that immunomodulatory agents such as beta-Interferon (IFN-beta) exert upon cytokine production in autoimmune disease such as multiple sclerosis remain incompletely understood. The recent development of techniques to directly assess cytokine production within peripheral blood leucocytes promises to advance this field. beta-Interferon treatment occasionally causes short-lived exacerbations of neurological dysfunction, often associated with systemic flu-like symptoms. Whereas these side effects usually occur and remit within the first few months of therapy, we have identified several patients who have developed symptoms many months after the onset of treatment. To begin to investigate the cause of these late onset exacerbations, we assessed the intracellular cytokine profiles of two patients, one stable on IFN-beta treatment and another experiencing side effects. The latter patient exhibited an increase in the percentage of monocytes that expressed g-Interferon after IFN-beta administration, whereas no such modulation was seen in the patient without side effects.

Adjuvants, Immunologic↗
PubMed2004

Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta.

Identifying effective treatment combinations for MS patients failing standard therapy is an important goal. We report the results of a phase II open label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-beta therapy and high brain inflammatory and clinical disease activity. Daclizumab was very well tolerated and led to a 78% reduction in new contrast-enhancing lesions and to a significant improvement in several clinical outcome measures.

Adult↗