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Results for “SCLEROSIS, MULTIPLE”

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PubMed1996

T-lymphocyte immunointerferon receptors in patients with multiple sclerosis.

Multiple sclerosis (MS) is a T-cell-mediated autoimmune demyelinating disease of the central nervous system (CNS), associated with an altered immunoregulation. Interferon (IFN)-gamma, also known as immune IFN, is a cytokine with several effects on the immune system. Specific IFN-gamma receptors have been found on human lymphocytes, as well as on other cell types (e.g. gliocytes), even in the CNS. The aim of the present study was to evaluate IFN-gamma binding on peripheral blood T-lymphocytes from MS patients, compared with those from healthy subjects. Thirty-two patients were selected according to the classical criteria for definite MS; as controls, 21 healthy subjects were studied. We have found that T-lymphocytes from MS patients bear a significantly smaller amount of IFN-gamma receptors than those from controls [Bmax: 568, 18 vs 708, 14 (mean, SE) receptors/ cell]. Such IFN-gamma binding sites are of the same type in patients and healthy subjects [Kd: 1.0, 0.05 vs 0.9, 0.02 (mean, SE) nM]. These findings are discussed in terms of immunopathogenesis of MS, since it has been reported that activated T-lymphocytes have decreased amounts of IFN-gamma receptors.

Adult↗

PubMed1995

Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis.

Multiple sclerosis (MS) is the most frequent, demyelinating disease of the central nervous system (CNS) in Northern Europeans and North Americans. Despite intensive research its etiology is still unknown, but a T cell-mediated autoimmune pathogenesis is likely to be responsible for the demyelination. This hypothesis is based both on findings in MS patients and studies of an experimental animal model for demyelinating diseases, experimental allergic encephalomyelitis (EAE). Experiments in EAE have not only demonstrated which myelin antigens are able to induce the demyelinating process but also have determined the characteristics of encephalitogenic T cells, that is, their fine specificity, major histocompatibility complex (MHC) restriction, lymphokine secretion, activation requirements, and T cell receptor (TCR) usage. Based on these findings, highly specific and efficient immune interventions have been designed in EAE and have raised hopes that similar approaches could modulate the disease process in MS. Although the examination of the myelin-specific T cell response in MS patients has shown parallels to EAE, this remains an area of intensive research because a number of questions remain. This review summarizes the important lessons from EAE, examines recent findings in MS, and discusses current concepts about how the disease process develops and which steps might be taken to modulate it.

Animals↗

PubMed2005

Emerging therapies in multiple sclerosis.

Multiple sclerosis (MS) is the most common neurological cause of disability in young people. The disease-modifying treatments, IFN-beta and glatiramer acetate, have been widely available over the last decade and have shown a beneficial effect on relapse rate and magnetic resonance imaging parameters of disease activity; however, their effect on disease progression and disability is modest. Therefore, the search for alternative treatment strategies continues. As understanding of the heterogeneous pathophysiology of MS has increased, emphasis has shifted to more selective therapy that targets components of the inflammatory cascade and the promotion of remyelination and neuroprotection. These agents target the blood-brain barrier, systemic immune dysfunction, local inflammation and neurodegeneration. Combination therapies are being investigated for patients who fail first-line treatments. Many new drugs are being developed and tested that address these issues with the aim of finding a more effective and convenient therapy. These include humanized monoclonal antibodies such as daclizumab (IL-2 antagonist), oral immunomodulators such as sirolimus and statins and neuroprotective agents such as NMDA antagonists and Na+-channel blockers. Many of the treatments discussed in this review are still at early stages of development, but provide exciting potential treatment options; others have proved disappointing in larger extended-phase studies.

Animals↗

PubMed1993

Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease characterized by focal demyelination of the white matter of the brain and spinal cord. Central nervous system damage appears to be mediated by infiltrating T lymphocytes and macrophages, and a central role for autoreactive CD4+ T cells has been proposed. However, the initial immune events that lead to the chronic process of MS remain unidentified. We now present evidence that a subset of T lymphocytes bearing gamma/delta T-cell antigen receptors has been activated in patients with recent-onset disease. Cells recovered from the cerebrospinal fluid of subjects with MS were cultured for short periods of time in medium supplemented with T-cell growth factors. Expansions of V delta 1 and V delta 2 T-cell receptor-bearing lymphocytes were found only in cell populations obtained from subjects with recent-onset disease. Similar populations were not expanded in subjects with chronic MS or other neurological diseases. Junctional region sequencing showed the expanded gamma/delta T cells to be oligoclonal in nature, suggestive of specific stimulation by antigen. These results reveal a fundamental difference in the immunopathogenesis of acute vs. chronic disease and provide additional insight into the autoimmune nature of MS.

Base Sequence↗

PubMed2004

Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis.

Multiple sclerosis (MS) is supposedly a T-cell mediated autoimmune disorder of the central nervous system. Cytokines and other molecules involved in the regulation of apoptosis are thought to be of importance for the pathogenesis of MS. In this study, the mRNA levels of interleukin 18 (IL-18), IL-1beta and their processing enzyme caspase-1 were quantified by a competitive RT-PCR method in unstimulated peripheral blood mononuclear cells (PBMCs) in MS patients never treated with disease modifying drugs. Western blot was used to support the expression pattern at the protein level. We found that the expression of caspase-1 and IL-18 was significantly increased in MS patients compared with healthy controls. Analysis of clinical subgroups revealed that caspase-1 was increased in all subgroups, whereas IL-18 was upregulated in chronic progression (P=0.001) and relapsing MS patients in remission (P=0.002) but not significantly during relapses (P=0.12). mRNA levels of IL-1beta were not significantly altered in MS except for a possible decrease in chronic progression (P=0.03). An increased IL-18 expression, potentially augmented at the mature protein level, may indicate a pathway worth considering in future therapeutic strategies in MS.

Actins↗

PubMed1999

A new cell enzyme-linked immunosorbent assay demonstrates gamma interferon suppression by beta interferon in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system of unknown etiology. Immune mechanisms involving the proinflammatory cytokine gamma interferon (IFN-gamma) are believed to play an important role in the pathogenesis of MS. IFN-beta-1b has been introduced as a treatment for MS and was found to reduce the number and severity of clinical exacerbations. To examine the influence of IFN-beta-1b on myelin basic protein (MBP)-specific and phytohemagglutinin-induced IFN-gamma production, we developed a cell-released capturing enzyme-linked immunosorbent assay (CRC-ELISA), which rapidly measures spontaneous and antigen- or mitogen-induced cellular IFN-gamma production. CRC-ELISA documented a significant MBP-specific T-cell response in the blood of untreated MS patients, as assessed by IFN-gamma production. This response was suppressed in MS patients treated with IFN-beta-1b. The present work confirms in vivo the in vitro suppressive effects of IFN-beta-1b on IFN-gamma production in MS. Moreover, it provides a powerful new technique for detection of cytokines.

Adult↗

PubMed2001

CD4+CD28- costimulation-independent T cells in multiple sclerosis.

Multiple lines of evidence suggest that CD4+ lymphocytes initiate autoimmune responses against myelin antigens in multiple sclerosis (MS). The increased frequency of activated myelin-specific cells in MS patients indicates that the activation of autoreactive cells represents a central event in the pathogenesis of the disease. We identified a CD4+ subpopulation that is characterized phenotypically by the persistent absence of surface CD28 expression and functionally by CD28-independent activation and Th1 cytokine secretion. Owing to their costimulation-independent activation and their expression of a full agonist signaling activation pattern, CD4+CD28- cells have the potential to initiate autoimmune responses in the central nervous system, a compartment devoid of professional antigen presenting cells. Long-term memory CD4+CD28- cells produce high amounts of IFN-gamma and maximally upregulate IFN-gamma and IL-12Rbeta2 chain expression in the absence of costimulation. They exhibit prominent growth characteristics and increased survival after activation, likely related to their persistent lack of CTLA-4 surface expression. The CD4+CD28- population is expanded in a subgroup of MS patients. Myelin basic protein-specific cells detected in this cell subset may play an important role in the inflammatory response within the central nervous system.

Adult↗

PubMed2002

Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis.

Multiple sclerosis (MS) patients of an inpatient rehabilitation program have been randomly assigned to an exercise training (MS-ET) or nontraining group (MS-NI). Before and after 4 weeks of aerobic exercise training, a graded maximal exercise test with measurement of gas exchange and a lung function test was administered to all 26 patients fulfilling the inclusion criteria. Activity level, fatigue and health perception were measured by means of questionnaires. Twenty-six healthy persons served as control group and were matched in respect of age, gender and activity level. Training intervention consisted of 5x30 min sessions per week of bicycle exercise with individualised intensity. Compared with baseline, the MS training group demonstrated a significant rightward placement of the aerobic threshold (AT) (VO2+13%; work rate [WR])+11%), an improvement of health perception (vitality+46%; social interaction+36%), an increase of activity level (+17%) and a tendency to less fatigue. No changes were observed for the MS-NI group and the control groups. Maximal aerobic capacity and lung function were not changed by either training or nontraining in all four groups. Overall compliance to the training program was quite low (65%), whereas incidence of symptom exacerbation by physical activity has been lower than expected (6%).

Adult↗

PubMed2001

Natural killer type 2 bias in remission of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease characterized by clinical relapse and remission. Because of the potential role of natural killer (NK) cells in the regulation of autoimmunity, we have examined cytokine profile and surface phenotype of NK cells in the peripheral blood of MS. Here we demonstrate that NK cells in the remission of MS are characterized by a remarkable elevation of IL-5 mRNA and a decreased expression of IL-12Rbeta2 mRNA, as well as a higher expression of CD95. Moreover, the NK cells from MS in remission produced much larger amounts of IL-5 than did those from controls after stimulation with phorbol myristate acetate (PMA) and ionomycin. These features are reminiscent of those of NK type 2 (NK2) cells that can be induced in a condition favoring functional deviation of T cells toward Th2. Remarkably, the NK cells lose the NK2-like property when relapse of MS occurs, but regain it after recovery. We also found that NK2 cells induced in vitro inhibit induction of Th1 cells, suggesting that the NK2-like cells in vivo may also prohibit autoimmune effector T cells. Taken together, it is possible that NK cells play an active role in maintaining the remission of MS.

Adult↗

PubMed2000

Pathogenic immunity in Theiler's virus-induced demyelinating disease: a viral model for multiple sclerosis.

Multiple sclerosis involves inflammatory immune responses in the central nervous system (CNS) and is considered as an autoimmune disease potentially associated with viral infection. The majority of experimental models rely heavily on the autoimmune components since similar diseases can be induced following immunization with various myelin antigens. A very attractive alternative model is the Theiler's murine encephalomyelitis virus-induced demyelinating disease. This disease is primarily a CD4+ T cell-mediated, inflammatory demyelinating disease induced following viral infection. Virus-specific inflammatory Th1 cell responses, rather than cytotoxic T lymphocyte response, play a critical role in the pathogenic immune responses. The major pathogenic epitopes have been identified and these are correlated with a Th1 type response to the epitopes following viral infection. In addition, the initial virus-specific immune response is followed by the autoimmune responses to myelin antigens. Assessment of cytokines produced locally in the CNS during the course of disease suggests involvement of inflammatory cytokines in the disease. Furthermore, the manipulation of inflammatory cytokine levels by administration of either recombinant cytokines or antibodies to the cytokines strongly influences the induction and/or progression of disease, supporting the importance of these inflammatory cytokines in this virus-induced demyelinating disease.

CD4-Positive T-Lymphocytes↗

PubMed1998

Dual implication of 2',3'-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is characterized by intra-blood-brain barrier immunoglobulin synthesis that persists lifelong. Subcellular fractionation and two-dimensional electrophoresis were used in conjunction with immune precipitation and immunoblotting to identify antigenic determinants for this immunoglobulin. We report that 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein associated with oligodendrocyte/myelin membranes, also present in lymphocytes and retina, is one major target for the humoral response. Antibodies to CNP are detected in sera of 74% of MS patients. The antibodies are IgM and are present in serum in high titer as well as in cerebrospinal fluid. The antibody response is temporally persistent, consistent with systemic immune activation and persistent antigenic stimulation. Moreover, CNP is isolated as an immune complex from MS brain. CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-amino acid extension at the amino terminus of CNPII; however, the antibody response is exclusively restricted to CNPI. In contrast, both isoforms bind the C3 complement, providing a plausible mechanism in MS central nervous system (CNS) for opsonization of myelin membrane CNP, mediated via the C3 receptor, and phagocytosis of CNP-Ig immune complexes, mediated by membrane Ig Fc receptors of macrophages and CNS microglia.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed2002

Expression and modulation of IFN-gamma-inducible chemokines (IP-10, Mig, and I-TAC) in human brain endothelium and astrocytes: possible relevance for the immune invasion of the central nervous system and the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mediated by blood-derived immune cells invading the CNS. This invasion could be determined by chemokines, and their role within the MS-affected brain is still poorly defined. We investigated the expression by RT-PCR and protein release by ELISA of the interferon-gamma (IFN-gamma)-inducible chemokines in human brain microvascular endothelial cells (HBMECs) and astrocytes. The monokine induced by IFN-gamma (Mig) behaves as a homing chemokine constitutively expressed in HBMECs and astrocytes, whereas the IFN-gamma-inducible 10-kDa protein (IP-10) and IFN-inducible T cell alpha-chemoattractant (I-TAC) are induced only after inflammatory stimuli. The biologic activity of IFN-gamma-inducible chemokines from an endothelial source was analyzed, and the transendothelial migration of activated lymphocytes was partly antagonized by specific antibodies, especially anti-Mig antibody. Our data highlight the capability of cells of the CNS to activate the chemoattractant machinery in a proinflammatory environment and in MS.

Antibodies↗

PubMed2006

Current status and future prospective of immunointervention in multiple sclerosis.

Multiple sclerosis (MS) is a complex neurological disorder characterized by inflammation and degeneration of the central nervous system, primarily involving the white matter. On the basis of a wide body of evidence in experimental models and in affected patients, several attempts to treat MS using drugs which modulate immune reactions have been performed or are currently ongoing. However, it should be stressed that inflammation does not have only a detrimental effect in MS. In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery. Due to the above, several trials with immunosuppressant drugs failed or were suspended because of unexpected worsening of the course of MS. The knowledge of MS immunopathogenesis is so rapidly evolving that any attempt to review it is in some way frustrating. On the other hand, this evolution is at the basis of the several new treatment options which can be hypothesized for this disease. The current status of immunosuppression in MS and the possible future development of MS treatment will be reviewed, with particular reference to those treatments which have already been tested in clinical trials and which are based on sound evidence of a putative interference with specific events occurring in MS, with the sparing of general immunity.

Azathioprine↗

PubMedDate not supplied

The immunopathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease that is triggered by unknown exogenous agents in subjects with a specific genetic background. Genes of the major histocompatibility complex class II region are the only ones that have been consistently associated with the disease. However, susceptibility is probably mediated by a heterogeneous array of genes, which demonstrate epistatic interactions. Furthermore, an infectious etiology of MS has been suggested, and it is likely that infectious agents shape the immune response against self-antigens. Composition of plaques, response to therapy, and data from animal models indicate that MS is mediated by myelin-specific CD4 T cells that, upon activation, invade the central nervous system and initiate the disease. Different patterns of tissue damage have been shown in active MS lesions, suggesting that the mechanisms of injury are probably distinct in different subgroups of patients. Heterogeneity in clinical characteristics, magnetic resonance imaging, and response to therapies support this notion. The experience gained during several pharmacological studies has improved our understanding of the pathogenesis of MS. New tools, such as gene expression profiling with cDNA microarrays and proteomics, together with advancements in imaging techniques may help us to identify susceptibility genes and disease markers, which may enable us to design more effective therapies and to tailor them according to different disease forms or stages.

Autoimmune Diseases↗

PubMed1996

Assessment of motor function in people with multiple sclerosis.

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) which predominantly affects young adults. In order to provide physiotherapy appropriate to the needs of individuals with MS, it is necessary to assess and evaluate the nature and degree of motor and functional deficits. The aim of this research was to develop a physiotherapy assessment which would consistently and objectively evaluate motor function in people with MS. The Motor Club Assessment (MCA), originally developed for use in stroke patients, was identified as exhibiting several features which were consonant with the required criteria. It was therefore modified for use in MS. The Amended MCA (AMCA) was tested for inter-rater agreement, which was found to be good for the lower limb motor section (weighted kappa = 0.80), the upper limb motor section (weighted kappa = 0.90), and the functional activities section (weighted kappa = 0.92). The internal consistency was high for the lower limb section (alpha = 0.97) and the functional activities section (alpha = 0.92), but could not be determined for the upper limb section due to a clear ceiling effect. The study demonstrated that the AMCA is a valid tool for assessment use by physiotherapists in MS patients, and that it has an acceptable level of reliability when used in a clinic setting by physiotherapists suitably experienced in the treatment of neurological patients.

Activities of Daily Living↗

PubMed2003

Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. No curative therapy is currently available, and approximately 80-90% of afflicted individuals are ultimately disabled. Interferon beta (IFNbeta) has been shown to decrease clinical relapses, reduce brain disease activity, and possibly slow progression of disability. However, the overall effect of treatment is partial and a substantial number of patients are considered poor or nonresponders. For this report, we tested the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients undergoing open-label IFNbeta therapy. Overall, no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points, were observed when stratified by any of the studied IFNAR gene polymorphisms. A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set. In addition, no significant association was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as studied by a family-based association analysis.

Adolescent↗

PubMedDate not supplied

Effects of dose titration on tolerability and efficacy of interferon beta-1b in people with multiple sclerosis.

Multiple sclerosis (MS) treatment with interferon beta is associated with well-known, easily managed adverse events, including influenza-like symptoms and injection-site reactions that decline over time. Initial dose titration has been shown to be one way of limiting these adverse events. Hence, a placebo-controlled, multicentre study of 98 patients was set up to explore whether a slower, four-stage, 4-week titration to a final dose of 250 microg subcutaneous interferon beta-1b might improve tolerability over a more rapid two-stage, 2-week titration in patients with relapsing-remitting MS. Frequency of adverse events was found to be similar between the two regimens: notably, no difference in the incidence of injection-site reactions, with a trend towards fewer influenza-like symptoms in the slow-titration group. Relative to placebo, significantly fewer patients receiving interferon beta-1b relapsed. This was more pronounced in the rapid-titration group than in the slow-titration group, showing that rapid and significant improvements in relapse rates were achieved within 90 days of starting interferon beta-1b. Although a rapid-titration regimen results in a quicker onset of clinical benefit, slow titration showed a non-significant trend towards reduced influenza-like symptoms.

Adjuvants, Immunologic↗

PubMed1996

Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating neurological disease in which autoreactive T lymphocytes sensitized to myelin components of the central nervous system are postulated to contribute to pathogenesis. The possible relevance of molecular mimicry between a human coronavirus and the myelin basic protein component of myelin in the generation of this autoimmune reaction was evaluated. Myelin basic protein- and virus-reactive T-cell lines were established from 16 MS patients and 14 healthy donors and shown to be mostly CD4+. In contrast to healthy donors, several T-cell lines isolated from MS patients showed cross-reactivity between myelin and coronavirus antigens. Overall, 29% of T-cell lines from MS patients (10 donors) but only 1.3% of T-cell lines from normal control subjects (2 donors) showed an HLA-DR-restricted cross-reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens. Moreover, reciprocal reactivities were only observed in MS patients (4 donors). This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease.

Adult↗