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Biomedical subjects

R Hohlfeld

Publications and source records attributed to R Hohlfeld.

At least 37 records · Page 2Linked to original sources
PubMed2003

The prospects for neuroprotection in MS.

In the past, neuroprotective therapies were mostly explored in neurodegenerative disorders like Parkinson's and Alzheimer's disease, and in ischaemic stroke. More recently, however, neuroprotection has been proclaimed an important goal for multiple sclerosis (MS) therapy. The basis for widening the scope of neuroprotection is evidence that neuronal and axonal injury are key features of MS lesions. In contrast with degenerative and ischaemic central nervous system injury, however, neurodegeneration in MS appears to be caused by an inflammatory, presumably autoimmune, process. The challenge for neuroprotection in MS is therefore greater than in degenerative and ischaemic disorders, because MS requires the combination of neuroprotective therapy and effective immunomodulation.

Humans↗
PubMed2002

A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.

BACKGROUND: Interferon beta-1a (IFNbeta-1a; Avonex) is effective for the treatment of relapsing MS; however, the optimal dose of IFNbeta-1a is not known. OBJECTIVE: To determine whether IFNbeta-1a 60 micro g IM once weekly is more effective than IFNbeta-1a 30 micro g IM once weekly in reducing disability progression in relapsing MS. METHODS: In a double-blind, parallel-group, dose-comparison study, 802 patients with relapsing MS from 38 centers in Europe were randomized to IFNbeta-1a 30 micro g (n = 402) or 60 micro g (n = 400) IM once weekly for >/=36 months. The primary endpoint was disability progression, defined as time to a sustained increase of >/=1.0 point on the Expanded Disability Status Scale (EDSS) persisting for 6 months. Additional endpoints included relapses, MRI, safety, immunogenicity, and subgroup analyses of disability progression. RESULTS: Both groups showed equal rates of disability progression (hazard ratio, 0.96; 95% CI, 0.77 to 1.20; p = 0.73). In both groups the proportion of subjects with progression of disability by 36 months estimated from Kaplan-Meier curves was 37%. No dose effects were observed on any of the secondary clinical endpoints. Only one MRI measure at one time point, number of new or enlarging T2 lesions at month 36 compared with month 24, showed a difference favoring the 60- micro g dose. Both doses were well tolerated; however, slightly higher incidences of flulike symptoms and muscle weakness were observed in the 60- micro g group. The incidences of neutralizing antibodies (titers >/= 20) were 2.3% in the 30- micro g group and 5.8% in the 60- micro g group. CONCLUSION: There was no difference between IFNbeta-1a 30 micro g and 60 micro g IM in clinical or MRI measures.

Adolescent↗
PubMed2002

[Multiple sclerosis. Therapeutic nihilism is the wrong approach here].

The standard treatment for acute multiple sclerosis relapses continues to be the intravenous administration of high-dose methylprednisolone. For prophylactic purposes, immunomodulatory therapy with interferon beta or glatiramer acetate, immunoglobulins or azathioprine. Studies have shown that interferon beta not only reduces the frequency of relapses by one-third, but also significantly delays the second relapse, provided it is administrated early, that is, immediately following the first relapse. The reduction in the patient's quality of life caused by the illness can be appreciably improved by a whole series of symptomatic treatments. The ideal situation is a cooperative effort by an interdisciplinary team.

Clinical Trials as Topic↗
PubMed2002

[Treatment of multiple sclerosis with glatiramer acetate. Current aspects of mechanisms of action, pharmacokinetics, adverse effect profile and clinical studies].

Glatiramer acetate (GA, Copaxone), a standardized mixture of synthetic polypeptides, has now been approved also in Germany for the treatment of relapsing-remitting multiple sclerosis (RR-MS). After it had been shown effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), it was evaluated in several clinical studies. In these studies, GA could alter the natural history of MS by both reducing the relapse rate and affecting disability. The clinical therapeutic effect of GA was consistent with the effect on magnetic resonance imaging-defined disease activity and burden in a recent multicenter study. As a daily standard dose, 20 mg of GA is injected subcutaneously. The induction of GA-reactive T-helper 2-like regulatory suppressor cells is thought to be the main mechanism of action. The most common adverse effects are mild injection site reactions. A remarkable but rare adverse effect is the only transient immediate post-injection systemic reaction manifested by flushing, chest tightness, palpitations, and dyspnea. Antibodies to GA which are induced during GA treatment do not interfere with its clinical effects.

Animals↗
PubMed2002

[Antegren (natalizumab). A promising new approach to therapy of multiple sclerosis].

Antegren (Natalizumab) is a humanized monoclonal antibody directed against alpha 4-integrin. This antibody binds to the alpha 4 subunit of alpha 4 beta 1-integrin (VLA-4) and alpha 4 beta 7-integrin on leukocytes and blocks the interaction of these integrins with their ligands (VCAM and MadCAM). Disruption of these cell adhesion molecule interactions inhibits the migration of leukocytes through the blood-brain barrier and the trafficking of leukocytes through the extracellular matrix. In clinical studies, short-term treatment of patients with multiple sclerosis (MS) with antegren resulted in a clear reduction of the number of new active brain lesions on magnetic resonance imaging (MRI). Antegren was safe and well tolerated. Two large phase III studies will help to determine the long-term effect of antegren on MRI and clinical outcome in relapsing-remitting MS patients.

Animals↗
PubMed2002

Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients.

We analysed the humoral immune response to glatiramer acetate (GA, Copaxone) in 20 multiple sclerosis patients treated with GA, 20 patients not treated with GA and 20 normal control subjects. Using an ELISA for detection of total GA-reactive immunoglobulins (all isotypes), all treated patients but also 3/20 untreated and 8/20 healthy subjects scored positive at 1:20 plasma dilutions. At higher dilutions, 5/20 treated patients and two healthy donors had relatively high levels of anti-GA antibodies. Isotype and IgG subclass analysis revealed that the two antibody-positive normal subjects had IgM and small titers of IgG1 or IgG2 antibodies. In contrast, 18 of 20 GA-treated patients, had low but significant titers of GA-reactive IgG4 antibodies. This finding is consistent with the previously described GA-mediated induction of T-helper 2 (TH2)-like regulatory T cells.

Adult↗
PubMed2002

The recognition, diagnosis and management of cerebral vasculitis: a European survey.

We have completed a survey of European neurological practice concerning cerebral vasculitis. Twenty-nine respondents from 15 countries provided information concerning the diagnosis and management. The results confirmed the anticipated low frequency of the disease, but also illustrated the power of any putative collaborative effort. Interestingly, there was a wide variation in clinical practice, in particular concerning the perceived importance of cerebral angiography as a diagnostic test and the very common use of steroids as first-line treatment, rather than more potent immunosuppressive agents. This variation is probably to be explained at least, in part, by the absence of any firm evidence base to inform clinical practice. A European collaborative effort--in which there has emerged considerable interest--offers a realistic opportunity to generate sound clinical evidence and thence scientifically robust practical guidelines.

Data Collection↗
PubMed2001

The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls.

Antibodies directed against the extracellular immunoglobulin (Ig)-like domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) and are implicated in the immunopathogenesis of multiple sclerosis (MS). In this study we investigated the epitope specificity of MOG(Igd)-specific autoantibodies immunopurified from MS patients (n=17) and normal healthy controls (HD; n=9). ELISA, using a panel of synthetic MOG(Igd) peptides, revealed that the epitope specificity of this response was heterogeneous in both groups. The most frequently recognised epitopes were located in amino acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular peptide specificity. We therefore investigated the ability of the immunopurified antibodies to recognise native MOG(Igd) expressed on at the membrane surface by FACS. Unexpectedly, antibodies fulfilling this essential criterion for a demyelinating antibody response were detected only in one of the MS samples. These results indicate that the epitope specificity of the human B cell response to MOG is not only heterogeneous, but may only mediate demyelination in a limited subset of MS patients.

Adolescent↗
PubMed2001

[Multiple sclerosis. Chlamydia hypothesis in debate].

Recently, an association between multiple sclerosis and Chlamydia pneumoniae infection has been suggested. Because standardized PCR protocols are lacking, a series of studies could not clarify whether C. pneumoniae is present in brain tissue and CSF of MS patients. Therefore, other studies focused on the humoral immune response against C. pneumoniae: 24% of MS patients, but only 5% of the control patients showed intrathecally produced antibodies against C. pneumoniae. If an infection with C. pneumoniae was involved in the pathogenesis of MS, one would expect that, in analogy to other infections of the CNS, the oligoclonal bands in the CSF of MS patients would recognize the responsible agent. However, the results we obtained by affinity-mediated immunoblots showed that the oligoclonal bands in the CSF of MS patients are not directed against Chlamydia antigen. In contrast to this, we found that the immunoglobulins in the CSF of neuroborreliosis patients reacted strongly against Borrelia antigen in the affinity-mediated immunoblots. In light of these results we assume that the intrathecal immunoglobulin production against C. pneumoniae is part of a polyspecific immune response. Thus, it is not likely that C. pneumoniae is causally linked to the pathogenesis of multiple sclerosis.

Antigens, Bacterial↗
PubMed2001

Treatment of multiple sclerosis with Copaxone (COP): Elispot assay detects COP-induced interleukin-4 and interferon-gamma response in blood cells.

Copolymer-1 (Copaxone or COP) inhibits experimental allergic encephalomyelitis and has beneficial effects in multiple sclerosis. There is presently no practical in vitro assay for monitoring the immunological effects of COP. We used an automated, computer-assisted enzyme-linked immunoadsorbent spot assay for detecting COP-induced interferon-gamma (IFN-gamma)- and interleukin-4 (IL-4)-producing cells and a standard proliferation assay to assess the immunological response to COP in peripheral blood mononuclear cells from 20 healthy donors, 20 untreated multiple sclerosis patients and 20 COP-treated multiple sclerosis patients. Compared with untreated and healthy controls, COP-treated patients showed (i) a significant reduction of COP-induced proliferation; (ii) a positive IL-4 Elispot response mediated predominantly by CD4 cells after stimulation with a wide range of COP concentrations; and (iii) an elevated IFN-gamma response partially mediated by CD8 cells after stimulation with high COP concentrations. All three effects were COP-specific as they were not observed with the control antigens, tuberculin-purified protein or tetanus toxoid. The COP-induced changes were consistent over time and allowed correct identification of COP-treated and untreated donors in most cases. We propose that these criteria may be helpful to monitor the immunological response to COP in future clinical trials.

Adult↗
PubMed2001

Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.

Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.

Animals↗
PubMed2001

Immunological update on multiple sclerosis.

The present review of the recent literature focuses on antigen-specific immune reactions in multiple sclerosis. New techniques have allowed precise quantitative analysis of the antigen-receptor repertoire of infiltrating T cells in the multiple sclerosis brain. Novel candidate autoantigens, including B-cell autoantigens, have been identified. 'Humanized' animal models allow the functional characterization of human immune molecules in vivo. Finally, several therapeutic trials have recently assessed the clinical benefit of selective immunotherapies.

Animals↗
PubMed2001

Risk-benefit assessment of glatiramer acetate in multiple sclerosis.

Glatiramer acetate, formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids. Glatiramer acetate has been shown to be effective in preventing and suppressing experimental autoimmune encephalitis (EAE), the animal model of multiple sclerosis (MS). Therefore it was tested in several clinical studies, where it was found to slow the progression of disability and to reduce the relapse rate and the magnetic resonance imaging (MRI)-defined disease activity and burden in relapsing-remitting MS. As a daily standard dose, 20mg of glatiramer acetate is injected subcutaneously. After injection, glatiramer acetate undergoes rapid degradation to amino acids and shorter peptides; so it is not possible to measure any systemic plasma concentrations or excretion rates. Two major mechanisms have been proposed to explain the effects of glatiramer acetate in EAE and MS: the induction of glatiramer acetate-reactive T helper 2 (Th2)-like regulatory suppressive cells and the interference with T cell activation as an altered peptide ligand. The most common adverse effects were mild injection site reactions (erythema, inflammation and induration). The most remarkable adverse event is the acute and transient immediate postinjection reaction manifested by flushing, chest tightness, palpitations and dyspnoea. Other reported adverse effects are transient chest pain and lymphadenopathy. Antibodies to glatiramer acetate induced during treatment do not interfere with its clinical effects. In several controlled clinical studies, glatiramer acetate has been shown to provide consistent, reproducible clinical benefits in the target population of patients with relapsing-remitting MS. The safety profile and risk-benefit ratio are excellent. Overall, glatiramer acetate is very well tolerated and has an excellent risk-benefit profile in patients with relapsing-remitting MS.

Clinical Trials as Topic↗