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Hans-Peter Hartung

Publications and source records attributed to Hans-Peter Hartung.

87 records · Page 5Linked to original sources
PubMed2003

Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection.

Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.

Animals↗
PubMed2003

Therapeutic strategies in the Guillain-Barré syndrome.

The Guillain-Barré syndrome (GBS) represents the prototypic immune-mediated peripheral neuropathy, which is now recognized as a group of conditions with diverse pathology and pathogenesis. The observation that plasma exchange and intravenous immunoglobulin result in clinical improvement, the presence of circulating antibodies targeting structures on peripheral nerve tissue in sera from GBS patients, and the deposition of immunoglobulins and complement demonstrated on myelinated fibers in nerve biopsies from affected patients point to a critical role of the humoral immune response in the pathogenesis of GBS. However, the observation of inflammatory infiltrates in nerve and the critical pathogenic role of neuritogenic T lymphocytes as demonstrated in the animal model support the concept that a disordered cellular immunity is also of critical importance in the pathogenesis of this neuropathy. Current treatment strategies are aimed at mitigating the harmful effects of the immune system on peripheral nerve. This review will address the rationale for immunotherapy in GBS based on experimental and immunologic studies of the pathogenesis of this disease.

Animals↗
PubMed2003

Current disease-modifying therapies in multiple sclerosis.

In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. Interferon beta has also been shown to be efficacious in secondary-progressive multiple sclerosis (SPMS) as well as in patients with isolated syndromes at risk to develop clinically definite multiple sclerosis (MS). Mitoxantrone is another disease-modifying drug that is available for SPMS and severe cases of RRMS. The clinical utility of disease-modifying agents in MS will be reviewed with respect to the anti-inflammatory, immunomodulatory, and immunosuppressive treatments that are currently available. Symptomatic therapies will not be considered.

Adjuvants, Immunologic↗
PubMed2003

Multiple paradigm shifts in multiple sclerosis.

PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. RECENT FINDINGS: The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. SUMMARY: Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.

Adjuvants, Immunologic↗
PubMed2003

Autoimmunity in the peripheral nervous system.

Autoimmune disorders of the peripheral nervous system (PNS) comprise a heterogeneous group of diseases that result from an aberrant immune response. Most of these disorders present severe morbidity and, in some cases, mortality. Even those conditions that are self-limited may display severe disability and necessitate hospitalization. Although their etiology remains elusive, there is increasing knowledge of the pathophysiological mechanisms causing tissue dysfunction and structural damage. The discovery of several mediators that constitute the molecular mechanisms of cell-cell and cell-extracellular-matrix interactions has revealed insight into various aspects of the neuroimmune interaction. Classic animal models associated with new genetic approaches have further increased our comprehension of the molecular pathways that regulate inflammatory disorders of the nervous system. The aim of this review is to describe various types and functions of the principal molecular components of the neuroimmune interaction and their importance in the principal autoimmune disorders of the PNS. We also provide an extensive description of clinical and pathological features of autoimmune disorders of the PNS, along with diagnostic and therapeutic implications.

Animals↗
PubMed2002

Immune mechanisms in chronic inflammatory demyelinating neuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated peripheral neuropathy. In recent years, the application of basic principles of general immunology has widened our understanding of the etiology and immunopathogenesis of this neuropathy. Although both cellular and humoral factors have been implicated, the data are still fragmentary and insufficient for a unified hypothesis. This review summarizes the present knowledge of the fundamental immune mechanisms related to the immunopathogenesis of CIDP and discusses the role of T cells, activated macrophages, cytokines, co-stimulatory molecules, and anti-myelin antibodies. An important factor in current approaches to the therapy of CIDP is the increasingly recognized concomitant axonal loss that occurs secondary to primary demyelination.

Antibody Formation↗
PubMed2002

Remyelinating strategies for the treatment of multiple sclerosis.

Demyelination is the pathological hallmark of multiple sclerosis (MS) lesions. The concept of remyelination has gained acceptance in recent years, but naturally occurring remyelination is incomplete. To improve repair processes, a number of strategies have been explored experimentally and clinical trials are being carried out. In principle, remyelination can be achieved by either promoting endogenous repair mechanisms or by providing an exogenous source of myelinating cells via transplantation. Both approaches have been successful in animal models of demyelination. Besides, many studies have elucidated principal mechanisms of oligodendrocyte biology and remyelination in the central nervous system (CNS). This progress in knowledge also allowed for more specific interventions. First clinical trials to enhance endogenous remyelination have been performed, unfortunately with disappointingly negative results. This illustrates that experimental data cannot be easily transferred to human disease, and more detailed knowledge on the regulatory mechanisms of remyelination in MS is required. Recently, the first MS patient received a transplant of autologous Schwann cells. Many other cell types are being studied experimentally, including stem cells. Despite the ethical problems associated with an embryonic cell source, new developments in stem cell biology indicate that adult stem cells or bone marrow-derived cells may substitute for embryonic cells in the future. In this review, we describe the current views on oligodendrocyte biology, myelination and remyelination, and focus on recent developments leading to reconstructing, remyelinating strategies in MS.

Axons↗
PubMed2002

Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy.

Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1). Serine palmitoyltransferase (SPT) is a heterodimeric molecule made up of two subunits, SPTLC1 and SPTLC2. Twelve index patients from families with presumed genetic sensory neuropathies were screened for SPTLC2 mutations. These families comprised six multigenerational families, including two previously reported families not linked to the SPTLC1 locus on chromosome 9 and one multigenerational family with a complicated hereditary sensory neuropathy syndrome with associated palmar plantar keratosis, ataxia and spastic paraplegia. The remaining families included one consanguineous family with presumed recessive HSN with two affected siblings, one case of congenital sensory neuropathy and four sporadic cases with adult onset sensory neuropathy. No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies.

Acyltransferases↗
PubMed2002

Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10.

Inflammatory cell recruitment is an important step in the pathogenesis of autoimmune demyelinating diseases of the PNS. Chemokines might play a critical role in promoting leucocyte entry into the nervous system during immune-mediated inflammation. Here, we report the expression pattern of the chemokine receptors CCR-1, CCR-2, CCR-4, CCR-5 and CXCR-3 in sural nerve biopsies obtained from patients with classical Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy and various non-inflammatory neuropathies. A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies and quantitation of labelled mononuclear cells revealed significantly elevated cell counts compared with controls. CCR-1 and CCR-5 were primarily expressed by endoneurial macrophages, whereas CCR-2, CCR-4 and CXCR-3 could be localized to invading T lymphocytes. Quantitative analysis revealed that CXCR-3 was expressed at highest numbers by infiltrating T cells compared with the other receptors. Thus, expression and distribution of CXCR-3 suggest a specific role of this receptor in chemokine-mediated lymphocyte traffic into the inflamed PNS tissue. Therefore, we further analysed the expression of its ligands interferon-gamma-inducible protein of 10 kDa (IP-10) and monokine induced by interferon-gamma (Mig). Significantly increased levels of IP-10 could be measured in the CSF of patients with inflammatory neuropathies, whereas no differences were observable for Mig. In situ hybridization for IP-10 mRNA mirrored the distribution of the cognate receptor within the inflamed PNS, and delineated endothelial cells as the primary cellular source of IP-10. Our results imply a pathogenic role for specific chemokine receptors and IP-10 in the genesis of inflammatory demyelinating neuropathies.

Adult↗
PubMed1999

Cloning, sequencing and molecular analysis of the Campylobacter jejuni groESL bicistronic operon.

The groESL bicistronic operon from the enteric pathogen Campylobacter jejuni was cloned and sequenced. It consists of two ORFs encoding proteins with molecular masses of 9.5 and 57.9 kDa, which showed a high degree of homology to other bacterial GroES and GroEL proteins. Northern blot analysis suggested that the groESL operon is transcribed as a bicistronic mRNA, and its steady-state level was markedly increased after temperature upshift. By primer extension assay, one potential transcription start point preceding the groESL genes could be demonstrated, and a putative promoter region compatible with both Escherichia coli and C. jejuni sigma70 consensus sequences was identified. A conserved inverted repeat, which is believed to be involved in the regulation of the groESL genes, was found between the -10 promoter box and the groES translation start site. The complete coding region of groEL was fused with pET-22b(+) and expressed in E. coli as a His6-tagged recombinant protein (rCjHsp60-His). After purification, the protein was recognized by an anti-HSP60 monoclonal antibody. ELISA and Western immunoblotting experiments showed that IgG and IgA antibody responses against rCjHsp60-His were not significantly increased in sera from 24 patients with sporadic Campylobacter infection when compared to sera from 16 healthy controls.

Amino Acid Sequence↗
PubMedDate not supplied

Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.

BACKGROUND: Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients. METHODS: 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy. FINDINGS: Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268). INTERPRETATION: Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

Adult↗