Biomedical subjects

Hans-Peter Hartung

Publications and source records attributed to Hans-Peter Hartung.

At least 55 records · Page 3Linked to original sources

PubMed2005

Statins--a cure-all for the brain?

'Statins' are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors - oral cholesterol-lowering drugs that are used to treat hypercholesterolaemia. It is widely accepted that statins have anti-inflammatory effects that are independent of their ability to lower cholesterol. Animal studies and observational clinical studies have indicated that statins might also be effective in treating certain neurological diseases - in particular, multiple sclerosis, Alzheimer's disease and ischaemic stroke. At present, however, results from ongoing prospective, randomized clinical trials are not available.

Animals↗

PubMed2005

Multiple sclerosis--novel insights and new therapeutic strategies.

PURPOSE OF REVIEW: This review focuses on novel aspects of the pathogenesis and advances in the therapy of multiple sclerosis (MS). RECENT FINDINGS: Recent observations suggest that early lesion development in MS may start in some forms with oligodendrocyte death and that inflammation appears as a secondary phenomenon only. The lack of sufficient remyelination in MS may be the result of a disturbed function of basic helix-loop-helix transcription factors. Clinically the identification of patients with a clinically isolated syndrome at high risk to develop clinically definite MS remains difficult; the predictive value of serum antibodies against myelin proteins remains controversial. The role of neutralizing antibodies in interferon therapy is discussed. New therapeutic approaches in MS are emerging. SUMMARY: The existing view on the pathogenesis of MS is still changing. The original assumption that cell-mediated demyelination is the key event in lesion development dictating clinical disability is critically reviewed and alternative pathways have been suggested. Oligodendrocyte death, axonal loss, the role of CD8 T lymphocytes, T regulatory cells, and B lymphocytes have come into the focus of newly evolving concepts in MS pathogenesis. A deepened understanding of the immunopathogenesis of this disease translates into innovative therapeutic approaches, such as blockade of alpha4 integrins by a humanized monoclonal antibody. In various animal models cell-replacement strategies yield promising results; however, turning these findings into an effective therapy in MS patients has a long way to go.

Animals↗

PubMed2005

Chronic inflammatory demyelinating polyneuropathy--update on pathogenesis, diagnostic criteria and therapy.

PURPOSE OF REVIEW: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a treatable but possibly underdiagnosed disorder of the peripheral nerve. This review covers the growing literature of the past years that deals with the pathogenesis, diagnostic criteria and treatment of CIDP. RECENT FINDINGS: The recent development of a biphasic animal model of experimental autoimmune neuritis may provide further insights into the pathogenesis of inflammatory demyelination of the peripheral nerve, such as in CIDP, and may allow the development of further innovative therapeutic strategies. In patients, the contribution of immune processes to the dysfunction in hereditary polyneuropathies and the association of hereditary neuropathy and CIDP has been described. Commonly used therapies remain corticosteroids, intravenous immunoglobulin and plasmapheresis; however, newer immunosuppressant approaches using mycophenolate mofetil or cyclosporin A, or immunomodulating therapies using monoclonal antibodies or interferons are presently under investigation. SUMMARY: The growing body of knowledge on the pathogenesis of CIDP and further diagnostic differentiation of subforms may help to develop more-effective therapies for CIDP in the next few years.

Anti-Inflammatory Agents↗

PubMed2005

Tumor necrosis factor-alpha-converting enzyme is expressed in the inflamed peripheral nervous system.

Tumor necrosis factor-alpha (TNF-alpha) is considered to play a critical role in the pathogenesis of immune-mediated inflammatory demyelinating disorders of the peripheral nervous system (PNS). Processing of membrane-bound inactive pro-TNF-alpha into the active soluble cytokine is mediated by a sheddase, the so-called TNF-alpha-converting enzyme (TACE), a member of the A Disintegrin and Metalloproteinase (ADAM) family. We explored the expression of TACE (ADAM-17) in sciatic nerves from Lewis rats with experimental autoimmune neuritis (EAN), an animal model of the Guillain-Barré syndrome (GBS), an immune-mediated polyradiculoneuropathy. To extend our study to human disease, sural nerve biopsies from GBS patients were investigated by immunohistochemistry. In EAN, T lymphocytes could be defined as the cellular source of ADAM-17 with peak expression levels at maximum clinical disease severity. Similarly, in human sural nerves, ADAM-17-expressing T cells could be localized primarily within the epi- and perineurium, whereas in control sections from patients with non-inflammatory neuropathies, no expression could be depicted. Our findings indicate that ADAM-17 is upregulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the PNS.

ADAM Proteins↗

PubMed2005

Evaluation of HMG-CoA reductase inhibitors for multiple sclerosis: opportunities and obstacles.

The disease-modifying agents currently used in the treatment of multiple sclerosis (MS) are not completely effective and are associated with adverse effects and high costs. Thus, alternative treatment options are highly desirable. HMG-CoA reductase inhibitors (statins), widely prescribed as cholesterol-lowering agents, may be a future treatment option for MS--either in an add-on therapy regimen or alone--as they have been shown to exhibit potent immunomodulatory effects. Several recent reports have demonstrated that HMG-CoA reductase inhibitors prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory mode of action of HMG-CoA reductase inhibitors that is comparable to that of interferon-beta, an established treatment for MS. An open-label clinical trial assessing simvastatin treatment in patients with MS revealed a significant decrease in the number and volume of new lesions, as assessed using magnetic resonance imaging, and a favourable safety profile. A large multicentre, placebo-controlled phase II clinical trial assessing atorvastatin in patients with a clinically isolated syndrome (i.e. a single clinical event that is indicative of demyelination, and that predisposes to the development MS) has recently been initiated. However, prospective placebo-controlled trials of HMG-CoA reductase inhibitors in definite MS are difficult to perform because of ethical and financial issues. Furthermore, overly optimistic reports in the popular media, as well as the often uncontrolled access to HMG-CoA reductase inhibitors by patients with MS, complicate the evaluation of HMG-CoA reductase inhibitors as a realistic future treatment option for MS.

Animals↗

PubMed2005

Tissue mRNA expression in rat of newly described matrix metalloproteinases.

Matrix metalloproteinases (MMPs) comprise a large group of endoproteinases that degrade all protein components of the extracellular matrix. Functionally, MMPs contribute to several different physiological as well as pathological conditions. The number of newly described MMPs has increased in recent years, although current knowledge about their expression pattern in various tissues remains incomplete. Here we analyzed the relative mRNA expression of the most recently described MMPs--MT5-MMP (MMP-24), MT6-MMP (MMP-25), MMP-27 and epilysin (MMP-28)--in a broad selection of rat tissues using real time-PCR. MMP-24 mRNA was found to be widely expressed with predominance in the central nervous system. MMP-25 mRNA, in contrast, exhibited peak expression levels in testis, kidney and skeletal muscle, differing from previously described distribution patterns in humans. mRNAs for MMP-27 and MMP-28 were generally expressed at a lower level. All four MMPs studied were detected at higher mRNA levels in bone and kidney, suggesting a possible role of these MMPs in physiological processes within these two organs. The present study highlights the differential distribution pattern of newly described MMPs among different tissues and underlines differences in the mRNA expression between different species.

Animals↗

PubMed2004

Osteopontin, a macrophage-derived matricellular glycoprotein, inhibits axon outgrowth.

Transected axons can regenerate beyond the site of injury in the peripheral but not in the central nervous system (CNS). Increasing evidence implicates inflammatory processes as modulators of axon regeneration after injury. In this study, we addressed a possible role of the matricellular glycoprotein osteopontin (OPN) using crush lesions of the optic and sciatic nerve as models of central and peripheral axotomy, respectively. OPN was strongly expressed by macrophages at the crush site in the optic but not sciatic nerve, indicating fundamental differences in the molecular programming of macrophages in both systems. Functionally, OPN exerted potent growth-inhibitory effects in an in vitro assay of axon outgrowth. Therefore, OPN expression by lesion-associated macrophages may contribute to the nonpermissive nature of the adult CNS preventing axonal regeneration following injury.

Animals↗

PubMed2004

Monocyte-derived HLA-G acts as a strong inhibitor of autologous CD4 T cell activation and is upregulated by interferon-beta in vitro and in vivo: rationale for the therapy of multiple sclerosis.

Peripheral antigen presenting cells (APCs) contribute to the maintenance of immune tolerance and are considered to play a critical role in promoting the (re)activation of autoreactive T cells in multiple sclerosis (MS). Interferon-beta (IFN-beta) is the principle immune-modulatory agent used in the treatment of MS, but its mechanism of action remains elusive. HLA-G is a non-classical MHC molecule (MHC class Ib) attributed chiefly immune-regulatory functions. We here investigated the role of monocyte-derived HLA-G in the immune-regulatory processes of MS and its implications for current immune-modulatory therapies. Monocytes constitutively express cell surface HLA-G1 and soluble HLA-G5. Comparison of monocytic HLA-G expression between patients with relapsing-remitting MS (n=17) and healthy donors (n=20) revealed significantly lower levels of HLA-G1 protein in MS patients. However, both groups showed a significant upregulation of HLA-G in response to IFN-beta in vitro. Serial measurements of HLA-G mRNA levels in MS patients before and during IFN-beta therapy corroborated the relevance of these results in vivo: 1 month after initiation of IFN-beta1b therapy (n=9), HLA-G1 and HLA-G5 were significantly increased compared to baseline levels and remained elevated during treatment for 6 months (n=3). Importantly, functional experiments demonstrated that monocyte-derived HLA-G inhibits both Th1 (IFN-gamma, IL-2) and Th2 (IL-10) cytokine production by antigen-stimulated autologous CD4 T cells. Soluble HLA-G added to antigen-specific T cell lines (TCLs) has similar effects on the release of cytokines and reduces T cell proliferation. Although both IFN-beta and IFN-gamma strongly enhance HLA-G1 and HLA-G5 expression by monocytes in vitro, IFN-beta leads to a stronger relative upregulation of HLA-G compared to classical MHC class I molecules than stimulation with IFN-gamma. Taken together, monocyte-derived HLA-G mediates the inhibition of autologous CD4 T cell activation and might be involved in immune-regulatory pathways in the pathogenesis of MS. We conclude that some desirable immune-modulatory effects of INF-beta might be accomplished via the upregulation of the immune-tolerogenic molecule HLA-G.

Adult↗

PubMed2004

Mechanisms of mitoxantrone in multiple sclerosis--what is known?

The recent publication of the MIMS-study (Mitoxantrone In Multiple Sclerosis) and the approval of several health authorities support the use of mitoxantrone in patients with active relapsing-remitting or secondary progressive multiple sclerosis. This review provides information on data thus far present on the putative mechanisms of action of mitoxantrone in the immunopathogenesis of this disabling disease.

Antigen-Presenting Cells↗

PubMed2004

In vivo MRI of brain inflammation in human ischaemic stroke.

Inflammation contributes to brain damage caused by ischaemic stroke. Macrophages, as the prevailing inflammatory cell population in stroke lesions, can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for MRI. In this single-centre open-labelled clinical phase II study we tested the potential of USPIO-enhanced MRI for macrophage imaging in human ischaemic stroke lesions. In a series of 10 consecutive patients, USPIO contrast agent was infused at the end of the first week after symptom onset. Two follow-up MRI scans were performed 24-36 h and 48-72 h after infusion. Two distinct components of USPIO-related signal changes were discernible, one associated with blood vessels and one representing parenchymal enhancement. Vessel-associated changes appeared as signal loss on T2/T2*-weighted images and decreased from the first to second scan after USPIO infusion, most likely reflecting a transient blood pool effect of the contrast agent. Conversely, parenchymal enhancement was mainly evident on T1-weighted images, increased over time, and matched with the expected distribution of macrophages. Importantly, USPIO-induced signal alterations throughout differed from signatures of conventional gadolinium-enhanced MRI, thus being independent from breakdown of the blood-brain barrier. We suggest that increasing USPIO-enhancement on T1-weighted images indicates brain infiltration by USPIO-laden macrophages. Thus, USPIO-enhanced MRI may provide an in vivo surrogate marker of cellular inflammation in stroke and other CNS pathologies.

Aged↗

PubMed2004

Biphasic form of experimental autoimmune neuritis in dark Agouti rats and its oral therapy by antigen-specific tolerization.

A new and biphasic form of experimental autoimmune neuritis (EAN) is described in dark agouti rats (DA rats) and is inducible by a single immunization with bovine peripheral nerve myelin (BPM) in complete Freund's adjuvant (DA-EAN). Animals develop a mild episode of disease; after recovery, 66-100% of the rats suffer from a more severe bout of EAN with paraparesis 25-30 days after immunization. By histology, DA-EAN is an inflammatory and demyelinating polyradiculoneuropathy virtually without axonal damage. Demyelination affects mainly spinal roots. This is also reflected by markedly increased F-wave latencies in nerve conduction studies of sciatic nerves. In sciatic nerves, inflammation and demyelination are found only focally and may be the histopathologic basis for conduction failure in some fibers. Immunologic investigations revealed stronger proliferative responses of DA than of Lewis rat lymph node cells to BPM and various peptides derived from the P2 protein. Proliferative and Th1-cytokine responses were particularly pronounced in spleen during the late phase of DA-EAN as compared to the monophasic EAN of Lewis rats. The data suggest that persistent lymphocyte proliferation with secretion of interferon (IFN)-gamma may be relevant for the relapsing course of DA-EAN whereas epitope spreading may explain the increased severity of the second bout of disease. The extended Th1 response in DA rats did not go along with a lack of downregulatory mechanisms, because the second DA-EAN attack was self-limited and splenocytes from DA rats produced considerable amounts of interleukin (IL)-10 and transforming growth factor (TGF)-beta. To substantiate further a functional immunoregulation in DA rats, we modulated DA-EAN by antigen-specific oral tolerization, which is known to involve active suppressor mechanisms. Preventive feeding of BPM in combination with cholera toxin (CT) induced a long-lasting resistance to DA-EAN. Even therapeutic administration of BPM or BPM/CT after onset of signs of disease significantly mitigated the further course of disease and prevented development of paraparesis. Because DA-EAN is easily inducible and leads consistently to relapses in most rats, it can be used for studies of immune factors that determine a relapsing course of autoimmunity. Furthermore, DA-EAN may serve as a model for relapsing inflammatory demyelinating polyneuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and for treatment studies. Our findings on effective prevention and therapy of DA-EAN by oral application of myelin/CT corroborate this form of immunomodulation as a treatment strategy for cell-mediated processes in chronic inflammatory neuropathies.

Administration, Oral↗

PubMed2004

Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases.

BACKGROUND: Interferon beta and statins are known to exert immunomodulatory actions by inhibiting gene transcription and translation of various proinflammatory molecules. Although interferon beta represents a mainstay in therapy for multiple sclerosis (MS), statins are considered a potential new approach in treating MS. OBJECTIVE: To investigate the effect of interferon beta and statins on the posttranslational activity of matrix metalloproteinases (MMPs) released from mononuclear cells in vitro that were obtained from patients with MS and healthy donors. DESIGN: Blood samples from 10 patients with a relapsing-remitting course of MS and 5 matched healthy individuals were studied. Peripheral blood mononuclear cells were isolated and stimulated with an antibody to CD3, phytohemagglutinin, or medium alone as a negative control. Proteolytic activity was investigated in the supernatants by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography in which gels were incubated with interferon beta or simvastatin during development. Zones of gelatin digestion were visualized and quantified. RESULTS: Incubation with interferon beta resulted in an inhibition of the gelatinolytic activity of MMP-9 and MMP-2. In contrast, simvastatin enhanced the proteolytic capacity of MMP-2 and MMP-9, with a statistically significant increase of MMP-2 activity when compared with findings in controls. There were no differences in the enzymatic response between patients with MS and healthy individuals. CONCLUSIONS: Interferon beta exhibits inhibitory effects at the posttranslational level of MMP activity, whereas simvastatin augments the proteolytic activity of MMP-2 and MMP-9, suggesting that statins exert anti-inflammatory and proinflammatory effects. This dual mechanism of action should be considered, given the recent interest in developing these drugs for treatment of MS.

Adult↗

PubMed2004

Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.

During recent years, novel insights in basic immunology and advances in biotechnology have contributed to an increased understanding of the pathogenetic mechanisms of immune-mediated disorders of the peripheral nervous system. This increased knowledge has an impact on the management of patients with this class of disorders. Current advances are outlined and their implication for therapeutic approaches addressed. As a prototypic immune-mediated neuropathy, special emphasis is placed on the pathogenesis and treatment of the Guillain-Barré syndrome and its variants. Moreover, neuropathies of the chronic inflammatory demyelinating, multifocal motor, and nonsystemic vasculitic types are discussed. This review summarizes recent progress with currently available therapies and--on the basis of present immunopathogenetic concepts--outlines future treatment strategies.

Animals↗

PubMed2004

[Cannabinoids in multiple sclerosis. Opportunity or hazard?].

Based on patient reports, animal data, and in vitro experiments, evidence has emerged indicating a positive effect of cannabinoids as symptomatic treatment of spasticity and pain in multiple sclerosis. The recently published CAMS study was the first multicenter, randomized, placebo-controlled phase III trial to examine the efficacy of cannabinoids on symptoms related to MS. There was no treatment effect of cannabinoids on the primary outcome measure, a difference in the reduction of spasticity as assessed by the so-called Ashworth score. In contrast, significant effects on patient-reported spasticity and pain were documented. A major problem of the study was a high degree of patient unmasking in the active treatment group. In this review, the results of the CAMS study are discussed in the context of previous trials, the putative mechanism of action of cannabinoids and their adverse event profile.

Animals↗

PubMed2004

European validation of a standardized clinical description of multiple sclerosis.

OBJECTIVES: The EDMUS system is a clinical database specifically tailored to the description of multiple sclerosis (MS). The EVALUED (Evaluation of the EDMUS system) study is an European project with two objectives: 1) to assess the inter-examiner reliability of the whole EDMUS system; 2) to validate the EDMUS-Grading Scale (EGS),which is a simplified version of the Kurtzke Disability Status Scale (DSS). METHODS: The protocol included 12 neurologists working in pairs within six European centres (Bari, Basel, Florence, London, Lyon, Würzburg). They assessed independently 30 MS patients in their centre, filling in the EDMUS forms. The reliability of the system was assessed on selected key items in the history of the MS onset, the clinical course and the disease course classification. The clinical examination of the patients permitted an assessment of the Kurtzke Expanded Disability Status Scale (EDSS) and the EGS. Level of agreement was measured in terms of kappa and weighted kappa indexes whenever appropriate. RESULTS: The study included 180 patients with definite or probable MS of whom 37% were males. Age was 35.8+/-9.6 years (mean +/- SD), disease duration 7.8+/-5.7 years, and mean EDSS score 4.1+/-2.2. The disease course was relapsing-remitting in 67%, secondary progressive in 22%, and progressive from disease onset in 11%. For key items of the history, the inter-examiner reliability level ranged from moderate to excellent. Concerning the disability scales, perfect agreement was reached in 59 % for EDSS and 78% for EGS. The close correlation and linear association (r=0.94, p<0.0001) between both scales demonstrated EGS's construct validity. CONCLUSION: The EDMUS system allows a consistent clinical description of MS using a common language. This standardized follow-up of MS patients is valuable especially in studies requiring a critical mass of informative patients.

Adult↗

PubMed2004

Biologic role of interferon beta in multiple sclerosis.

The mode of action of interferon-beta (IFNbeta) as a therapeutic agent for multiple sclerosis is still insufficiently elucidated. Of the known immunomodulatory effects of IFNbeta, those that seem important are its [1] effects on the production of cytokines by T helper lymphocytes, [2] antagonistic effect against some of the proinflammatory and immunoregulatory effects of IFNgamma, [3] inhibitory effect on resistance of T lymphocytes to apoptotic signals, [4] inhibitory effect on the production of matrix metalloproteases, and [5] modulatory effect on the expression of adhesion molecules and chemokines. The relative importance of each of these actions is presently unknown, and still other actions of IFNbeta may be at play. The possibility that therapeutic IFNbeta compensates for a lack of endogenous IFNbeta production is discussed.

Animals↗

PubMed2004

Assessment and management of neutralizing antibodies in patients with multiple sclerosis.

The development of neutralizing antibodies (NAbs) to interferon beta (IFNbeta) products during treatment of MS poses a challenge for clinicians. Given the impact of NAbs on the clinical efficacy of IFNbetas, the immunogenicity of different IFNbeta products should be one of the factors that neurologists consider in the treatment of patients with MS. However, no clear guidelines are available for the practicing neurologist concerning which patients should be tested for NAbs and how to clinically manage patients who develop NAbs. This article summarizes the content of this supplement, discusses issues related to measuring NAbs in clinical practice, and gives practical alternatives for managing MS in patients who develop NAbs during IFNbeta therapy.

Antibodies↗

PubMed2004

What do we know about the mechanism of action of disease-modifying treatments in MS?

Multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system (CNS), 2 results in damage to axons and their surrounding myelin sheath. The exact cause of inflammation remains unclear, but an autoimmune response directed against CNS antigens is suspected. MS can affect the brain, optic nerve and spinal cord, thus causing many neurological symptoms. These can include limb numbness or weakness, sensory or motor changes, ataxia, blurry vision, painful eye movements, bladder and bowel dysfunction, decreased memory, fatigue and effective disorders. This article will include a concise overview of the pathogenesis of MS in order to set the stage for subsequent discussion of the mechanisms of action of disease-modifying treatments, and whether these should influence our treatment choices. Although the exact pathogenesis of MS is not fully understood, current knowledge has already led to the development of effective treatments, namely interferon (IFN) 3 and glatiramer acetate, both of which have been shown to reduce relapse rates, while IFN 3- 1 a also reduces confirmed disability progression. Further increases in our understanding of the pathogenesis of MS are likely to assist in the identification of new targets for disease-modifying therapies and in the optimisation of current treatments..

Antigen-Presenting Cells↗