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Hans-Peter Hartung

Publications and source records attributed to Hans-Peter Hartung.

At least 37 records · Page 2Linked to original sources
PubMed2005

Therapeutic role of mitoxantrone in multiple sclerosis.

Mitoxantrone is approved by several health authorities for treatment of active forms of relapsing-remitting or secondary progressive multiple sclerosis (SPMS). This review provides an outline on relevant preclinical as well as clinical studies, places mitoxantrone in the context of other therapeutic approaches against multiple sclerosis (MS), and discusses relevant side effects. The current knowledge of the putative mechanisms of action of the compound is discussed.

Humans↗
PubMed2005

Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale.

The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Animals↗
PubMed2005

Putative mechanisms of action of statins in multiple sclerosis--comparison to interferon-beta and glatiramer acetate.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-beta. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-beta and glatiramer acetate (GA).

Adjuvants, Immunologic↗
PubMed2005

Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients.

B-Lymphocytes↗
PubMed2005

Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations.

In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

Disease Progression↗
PubMed2005

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.

Adult↗
PubMed2005

Acute disseminated encephalomyelitis: an update.

Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms. Paraclinical tests may support the diagnosis. Particularly helpful are acute signs of newly developed extensive, multifocal, subcortical white matter abnormalities on magnetic resonance images of the brain. The cerebrospinal fluid may disclose a mild lymphocytic pleocytosis and elevated albumin levels. Oligoclonal bands are not always present in ADEM and, if so, may be transient. The major differential diagnosis of ADEM is multiple sclerosis. Treatment options for ADEM consist of anti-inflammatory and immunosuppressive agents. In general, the disease is self-limiting and the prognostic outcome favorable. In the absence of widely accepted clinical or paraclinical diagnostic guidelines, a number of recently conducted observational case series have substantially broadened our understanding about the clinical phenotype, diagnosis, and prognosis of ADEM.

Acute Disease↗
PubMed2005

Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.

Recently, two missense mutations (N88S, S90L) in the Berardinelli-Seip congenital lipodystrophy gene have been identified in autosomal dominant distal hereditary motor neuropathy and Silver syndrome. We report the phenotypic consequences of the N88S mutation in 90 patients of 1 large Austrian family and two unrelated German families. Variation in the clinical and electrophysiological phenotype enabled us to distinguish six subtypes. In 4.4%, the disorder was not penetrant. Twenty percent of the patients were subclinically affected; some of these patients could only be detected by pathological nerve conduction studies. A distal hereditary motor neuropathy type V phenotype characterized by predominant hand muscle involvement was found in 31.1%, whereas 14.5% showed typical Silver syndrome with amyotrophy of the small hand muscles and spasticity of the lower extremities. Moreover, the phenotype present in 20% was compatible with Charcot-Marie-Tooth disease. In 10%, the clinical diagnosis of pure or complicated hereditary spastic paraparesis was made. Electrophysiological studies showed an axonal neuropathy but also chronodispersion of compound motor action potentials and conduction blocks. Sensory nerve conduction studies were rarely pathological. Our study indicates that the dominant N88S mutation in the Berardinelli-Seip congenital lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders.

Action Potentials↗
PubMed2005

Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria".

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Humans↗
PubMed2005

Early treatment and dose optimisation BENEFIT and BEYOND.

The use of interferon beta (IFNbeta) in the treatment of multiple sclerosis (MS) has not changed greatly since its introduction. However, two new treatment paradigms have recently emerged-initiation of treatment as early in the course of the disease as possible and the use of higher doses with greater frequency to gain maximum therapeutic effect. The rationale for early treatment comes from evidence showing that early and irreversible pathology exists in very early stages of relapsing remitting MS (RRMS) often before significant disability is apparent and continues during remission. In addition, irreversible axonal damage begins early in the course of MS. Two relatively short-term studies indicate that it is possible to delay the onset of MS by early treatment with low-dose IFNbeta-1a. The BENEFIT (BEtaferon/Betaseron in Newly Emerging MS For Initial Treatment) study is being undertaken to investigate whether early intervention with a high-dose and more frequent administration of IFNbeta-1b (250 microg [8 MIU] every other day [eod]) has the ability to affect long-term clinical and magnetic resonance imaging (MRI) outcomes even more favourably. In addition, together with its follow-up study, BENEFIT will address the open question of long-term effects of early treatment on disease progression. Results from the pivotal IFNbeta-1b study, together with data from PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) showed the presence of a dose-response relationship for IFNbeta in the treatment of RRMS. This finding was confirmed by the results of INCOMIN (INdependent COMparison of INterferons) and EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy), direct comparative studies of high-dose (250 microg IFNbeta-1b, 44 microg IFNbeta-1a), high-frequency versus lower dose (30 microg IFNbeta-1a) and less frequent IFNbeta regimens. Results from a pilot study in patients with RRMS have indicated that increasing the dose of IFNbeta-1b to 500 microg (16 MIU) had a more pronounced biological effect compared with the standard 250 microg dose. The BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose) study is being undertaken to investigate whether IFNbeta-1b 500 microg eod is superior to the standard 250 microg eod dose in treatment-naïve patients with RRMS. A third treatment arm will provide a comparison with glatiramer acetate 20mg subcutaneously once daily.

Adjuvants, Immunologic↗
PubMed2005

Purely systemically active anti-inflammatory treatments are adequate to control multiple sclerosis.

Collective evidence supports the notion that multiple sclerosis is principally an autoimmune disease. Much of it stems from models of experimental autoimmune encephalomyelitis, generated by inoculation of animals with central nervous system antigens such as MBP, PLP, S100 and MOG or peptides thereof. Different ways of immunization and different animal species and strains mirror different aspects of the neuropathology of multiple sclerosis, such as inflammation, demyelination or axonal damage, and reflect different clinical courses. In all these models, the first immune reactions take place in lymph nodes from which immune cells migrate into the circulation and then to the central nervous system. Adoptive transfer of myelin-reactive T cells from these animals produces pathology and disease in the central nervous system of naïve healthy recipients. In the human disease, autoreactive T and B cells specific for a variety of central antigens are present in the immune repertoire. These cells appear to be activated in the periphery through a number of mechanisms which causes them to home to the central nervous system. Contact with the local immune circuitry of the brain stimulates clonal expansion of autoreactive T cells, initiating a cascade of immuno-inflammatory events in situ. Numerous ways of disrupting this complex sequence of events, either by non-specific immunosuppression or by targeting specific checkpoints, abrogate or ameliorate disease in animal models. All approved disease-modifying drugs have an impact on components of the systemic immune compartment. All have been shown to reduce the number of gadolinium-enhancing T1 lesions observed with magnetic resonance imaging, an index of acute inflammatory invasion of the central nervous system.

Animals↗
PubMed2005

Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro.

Mitoxantrone is an anti-neoplastic anthracenedione derivative that, based on its immunosuppressive properties, is approved for the treatment of severe forms of relapsing-remitting or secondary progressive multiple sclerosis (MS). Whether the beneficial clinical effects of mitoxantrone in MS are due to a broad immunosuppression, or whether there is a specific mechanism of action remains unknown. Peripheral blood mononuclear cells (PBMCs) from untreated or interferon-beta-treated patients with MS or from healthy donors were stimulated in the presence or absence of mitoxantrone. Irrespective of the source of the cells and the cellular phenotype, mitoxantrone inhibited proliferation of activated PBMCs, B lymphocytes, or antigen-specific T-cell lines (TCLs) stimulated on antigen-presenting cells (APCs) in a dose-dependent manner. For functional analysis, TCLs or APCs were incubated separately with mitoxantrone. Pre-incubation of APC more effectively impaired TCL proliferation than pre-incubation of TCLs. Production of cytokines, expression of activation markers, matrix metalloproteinases, and chemokine receptors were not influenced substantially by mitoxantrone. In contrast, in dendritic cells (DCs), mitoxantrone interfered with the antigen-presenting capabilities. For evaluation of apoptotic cell death of target cells, annexin-V-conjugates and a DNA fragmentation assay were applied. Mitoxantrone induced apoptosis of PBMCs, monocytes and DCs at low concentrations, whereas higher doses caused cell lysis. Our observations suggest that the beneficial effects of mitoxantrone in MS result (i) from its immunosuppressive action based on nonspecific cytotoxic effects on lymphocytes, (ii) by inducing programmed cell death of professional APCs, such as DCs.

Adult↗
PubMed2005

Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis.

Interferon beta was the first therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (MS) more than 10 years ago. Interferon beta reduces relapse rates and disease burden and activity, and it may have beneficial effects on the progression of long-term disease disability. The occurrence of neutralising interferon-beta antibodies has been postulated as a possible cause of the failure of interferon beta in some patients with MS. Here we discuss the basic mechanisms that may account for the generation of an interferon-beta antibody response and its biological implications. We review the evidence for neutralising antibodies as a consequence of interferon-beta treatment, and discuss the implications for the treatment of MS. Strategies to assess and manage the long-term impact of neutralising antibodies will be outlined.

Animals↗