PubMed Health⌕ Search

Biomedical subjects

Gavin Giovannoni

Publications and source records attributed to Gavin Giovannoni.

At least 19 recordsLinked to original sources
PubMed2006

The role of antibody affinity for specific antigens in the differential diagnosis of inflammatory nervous system disorders.

Affinity maturation has previously been shown with assays for total IgG for specific antigens using the technique of competition by chaotropic ions. We have extended this technique to individual clones and followed the maturation of clones during the course of herpes encephalitis. This has important implications for our understanding of the pathogenesis of multiple sclerosis.

Animals↗
PubMed2006

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Adolescent↗
PubMed2006

Multiple sclerosis cerebrospinal fluid biomarkers.

Cerebrospinal fluid (CSF) is the body fluid closest to the pathology of multiple sclerosis (MS). For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP) and neurofilaments (NF) have advantages over intermittent inflammatory markers.

Biomarkers↗
PubMed2005

Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease.

Infection with the Group A Streptococcus (GAS) can result in immune mediated brain disease characterised by a spectrum of movement and psychiatric disorders. We have previously described anti-neuronal antibodies in patients that bind to a restricted group of brain antigens with molecular weights 40 kDa, 45 kDa (doublet) and 60 kDa. The aim of this study was to define these antigens using 2-dimensional electrophoresis or ion exchange and hydrophobic interaction chromatography, followed by mass spectrometry. The findings were confirmed using commercial antibodies, commercial antigens and recombinant human antigens. The autoantigens were neuronal glycolytic enzymes--NGE (pyruvate kinase M1, aldolase C, neuronal-specific and non-neuronal enolase). These are multifunctional proteins that are all expressed intracellularly and on the neuronal cell surface. On the neuronal plasma membrane, NGE are involved in energy metabolism, cell signalling and synaptic neurotransmission. Anti-NGE antibodies were more common in the 20 unselected post-streptococcal CNS patients compared to 20 controls. In vitro experiments using cultured neurons showed that commercial anti-NGE antibodies induced apoptosis compared to blank incubation and control anti-HuD antibody. GAS also expresses glycolytic enzymes on cell surfaces that have 0-49% identity with human NGE, suggesting molecular mimicry and autoimmune cross-reactivity may be the pathogenic mechanism in post-streptococcal CNS disease.

Animals↗
PubMed2005

Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis.

OBJECTIVES: The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol. PATIENTS AND METHODS: In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent). RESULTS: By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS). CONCLUSION: We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

Adult↗
PubMed2005

No evidence for production of intrathecal immunoglobulin G against Acinetobacter or Pseudomonas in multiple sclerosis.

The production of oligoclonal, polyspecific immunoglobulin G is characteristic of multiple sclerosis (MS), yet no pathogen has been identified as an infectious agent. Recent studies have proposed Acinetobactercalcoaceticus and Pseudomonas aeruginosa as candidate organisms, on the basis of a sequence homology between a bacterial enzyme and bovine myelin basic protein. To investigate this, we looked for specific, high-affinity immunoglobulin G against these pathogensin paired serum and cerebrospinal fluid from MS patients compared to other neurological diseases. We found no greater incidence of high-affinity antibodies against the organisms studied in MS vs. other neurological diseases, and so conclude that A. calcoaceticus and P. aeruginosa are unlikely to be implicated in the pathogenesis of MS.

Acinetobacter↗
PubMed2005

Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.

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.

Consensus Statements as Topic↗
PubMed2005

Gluten Ataxia and Post-Streptococcal Central Nervous System Syndromes: Emerging Immune-mediated Disorders of the Central Nervous System?

There is an "emerging concept" that central nervous system dysfunction can be caused by an aberrant immune response triggered by exogenous antigens such as the food allergen gluten or streptococcal infection. The hypothesis of a gluten sensitive ataxia remains unproven, but is worthy of consideration. The data in support of this hypothesis require critical review before any treatment recommendations can be formulated. The idea that anti-gliadin antibody seropositivity per se justifies the term "gluten sensitivity" is important because it offers potential therapeutic possibilities, including simple exclusion diets, for patients with anti-gliadin antibody-associated ataxia. Post-streptococcal basal ganglia dysfunction has various manifestations, all of which fall into a relatively well-defined symptom complex or syndrome. Anti-basal ganglia antibodies that are associated with serologic evidence of recent streptococcal infection are a potential diagnostic marker for this group of disorders, which includes Sydenham's chorea (SC) as the prototype. More recently subjects with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, Tourette's syndrome, obsessive-compulsive disorder and other movement disorders have been described in association with anti-basal ganglia antibodies. The apparent overlap between the clinical phenotype of SC, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, Tourette's syndrome, and obsessive-compulsive disorder suggests that they may represent one disease entity. The current working hypothesis is that antibodies induced in response to streptococcal infection cross-react with antigenic determinants in the basal ganglia resulting in basal ganglia dysfunction. Although the experimental evidence is incomplete, there is sufficient evidence to support immune-mediated basal ganglia dysfunction as an emerging clinical entity. This has important implications for the diagnosis and treatment of subjects with these disorders. The latter includes the judicious use of antibiotic prophylaxis and immunomodulatory therapies. Apart from the diagnosis and management of SC, no consensus exists regarding the diagnosis and management of the other clinical entities within this group of disorders.

Journal Article↗
PubMed2005

Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis.

To date there has been poor translation of immunotherapies from rodent models to treatment of progressive multiple sclerosis (MS). In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T cells followed by intravenous (i.v.) myelin antigen administration, established relapsing disease in EAE can be effectively silenced. However, when treatment was initiated in late stage chronic-relapsing disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression shown by a deterioration in mobility and development of spasticity and indicates that targeting relapsing, immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.

Adoptive Transfer↗
PubMed2005

Soluble adhesion molecules in acute disseminated encephalomyelitis.

Soluble adhesion molecules are overexpressed in neuroinflammatory disorders. Their synthesis parallels that of their membrane-bound counterparts, which modulate lymphocyte transmigration through the blood-brain barrier. Blood-brain barrier cellular migration may be essential in the evolution of postinfectious inflammatory central nervous system disease. The serum levels of soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E-selectin were measured in 12 children with acute disseminated encephalomyelitis and in two control groups (35 healthy and 35 affected by noninflammatory neurologic diseases) of similar age. In patients with acute disseminated encephalomyelitis, soluble E-selectin serum levels were significantly higher (median 113 ng/mL, range 54-144) than in both control groups (median 44, range 31-63, and median 58, range 43-89, respectively; one-way analysis of variance, P < 0.0001); a statistical trend for higher levels of soluble intercellular adhesion molecule-1 was observed in acute disseminated encephalomyelitis subjects, whereas soluble vascular adhesion molecule-1 titers did not differ between the three groups. The specific role played by each of these molecules in lymphocyte extravasation and the differential cytokine modulation of their expression might explain the result. Further larger studies are required including serial measurements and cerebrospinal fluid analysis.

Adolescent↗
PubMed2005

Spread of T lymphocyte immune responses to myelin epitopes with duration of multiple sclerosis.

Although the primary cause of multiple sclerosis (MS) is unclear, evidence supports a role for autoimmune attack of myelin by T lymphocytes. However, it has been difficult to relate patterns of autoimmunity to pathogenesis. In mouse models, the case has been made for relapsing and remitting disease driven by epitope spread: an initial lesion leads to presentation of central nervous system antigens, in turn triggering the next wave of autoimmune T cells of different specificity, the response thus broadening. Few studies have been done to determine whether these events could be important over the longer time scale of human disease. We compared T cell responses with a panel of myelin epitopes in clinically isolated syndrome patients with a first attack, patients with MS with a mean disease duration of 0.95 years, and patients with MS having a mean disease duration of 15.9 years. T cells from patients with long-term disease recognize more myelin epitopes than patients with recent-onset disease. The epitope myelin basic protein 131-149, in particular, was more commonly recognized by patients with long-term disease. The data support the notion that the T cell response in MS broadens with time and is thus implicated in the ongoing pathogenic process. However, there was no clear correlation between disease severity and number of epitopes recognized. This may argue against a simple causal role of epitope spread in driving progression, as has been suggested in experimental allergic encephalomyelitis.

Adult↗