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Biomedical subjects

M Stangel

Publications and source records attributed to M Stangel.

At least 19 recordsLinked to original sources
PubMed2006

Blockade of chemokine signaling in patients with multiple sclerosis.

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Central Nervous System↗
PubMed2006

[Concepts of lesion development in multiple sclerosis. Current approaches and clinical-therapeutic implications ].

The pathogenesis and development of lesions in multiple sclerosis (MS) are still unexplained and are the subject of some controversy. On the basis of histopathological analysis of a small set of MS cases, a recently published study postulates primary oligodendroglial damage as the initiator of MS lesions, with infiltration of leukocytes into the central nervous system (CNS) as a secondary phenomenon. In this paper we outline the current controversial discussion and different concepts of lesion development in MS. We conclude that demyelination can result from different pathogenic mechanisms, with either primary autoimmune inflammation or primary oligodendroglial damage and a secondary inflammatory reaction. Lesions can be divided into four subtypes (patterns I-IV) on the basis of histopathological characteristics, which supports the idea that MS lesions develop in different ways. These new aspects may have major implications for treatment. However, except in a few specific forms, most MS patients cannot currently be assigned to one of these lesion subtypes by means of clinical and paraclinical parameters. Without this, individual treatments tailored to the pathogenesis will not be possible.

Encephalitis↗
PubMed2006

Expression of chemokine receptors on peripheral blood mononuclear cells of patients with immune-mediated neuropathies treated with intravenous immunoglobulins.

Intravenous immunoglobulin (IVIg) is an efficacious treatment for immune-mediated neuropathies like Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP), and multifocal motor neuropathy (MMN). In the pathogenesis of immune-mediated neuropathies chemokines and their receptors play a crucial role. Using flow cytometry we examined whether IVIg modulates chemokine expression repertoires of T cells and monocytes. The expression of inflammatory chemokine receptors CCR1, CCR2, CCR4, CCR5, CCR6 and CXCR3 was investigated on circulating T-cell subsets, and CCR1, CCR2 and CCR5 on circulating monocytes before and after IVIg treatment in patients with immune-mediated neuropathies (MMN, n = 7; GBS, n = 1; CIDP, n = 2). Furthermore, the homing potential of T cells was analyzed by the expression of CCR7, a chemokine receptor known to be utilized by mature T cells to recirculate into secondary lymphoid organs. In contrast to studies in chronic heart failure, no differences in expression patterns before and after IVIg treatment of any of the investigated chemokine receptors were found. Furthermore, the proportion of CD45RO-positive CD4+ or CD8+ T-cell subsets was not changed by IVIg treatment. Thus, we concluded that modulation of the expression of chemokine receptors on circulating leukocytes by IVIg is not a mode of action in immune-mediated neuropathies.

Adult↗
PubMed2006

Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis.

During the last decade immunomodulatory treatments have been shown to influence the natural course of multiple sclerosis (MS). However, demyelination in the central nervous system (CNS) still occurs and repair mechanisms are incomplete leading to neurological deficits. Currently, there is no therapy available to promote remyelination and thus enhance repair mechanisms. Both immunoglobulins directed against spinal cord homogenate and polyclonal immunoglobulins for intravenous use (IVIg) have been shown to support remyelination in the animal model of Theiler's virus encephalomyelitis (TMEV). Further studies have identified monoclonal antibodies that lead to remyelination in TMEV and a toxic demyelination model using lysolecithin. The shared characteristics of these monoclonal antibodies are an IgM isotype and the capacity to bind oligodendrocytes, independent of epitope specificity. Recently, two human monoclonal antibodies with remyelinating properties were described. Clinical trials with IVIg have so far failed to demonstrate clinical improvement in MS patients, but these studies only employed IgG preparations. However, recent experimental data both in vivo and in vitro underline the importance of IgM for remyelination. Thus future clinical trials are needed to evaluate the remyelination potential of IgM in human diseases. The design of monoclonal antibodies capable of promoting remyelination is a telling example for the design of new specific therapies derived from biological products like polyclonal immunoglobulins.

Animals↗
PubMed2005

[High-dose intravenous immunoglobulins in the treatment of multiple sclerosis. An update].

The immunomodulatory treatment of multiple sclerosis (MS) with high-dose intravenous immunoglobulins (IVIg) has been discussed with some controversy in the context of evidence-based medicine. The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIg treatment in MS. Here we summarize and critically discuss the new data in the context of previous studies on this treatment. In relapsing-remitting MS, IVIg remain a second-line treatment when other licensed treatments are not possible. Currently there is no role for IVIg in secondary progressive MS. Similarly, the use of IVIg during an acute relapse shows no benefit in addition to standard steroid treatment. The initiation of IVIg therapy after a clinically isolated syndrome has delayed the occurrence of definite MS, and this may become a new indication. Furthermore, previous data suggesting that IVIg can reduce the incidence of postpartal relapses have been substantiated. However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIg in MS are supported by the new data.

Clinical Trials as Topic↗
PubMed2005

[Cannabinoids in multiple sclerosis -- therapeutically reasonable?].

For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies. Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS. Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS. Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms. Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties. However, results from clinical trials do not allow the recommendation for the general use of cannabinoids in MS. This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS.

Cannabinoids↗
PubMed2005

Intravenous Immunoglobulins in MS.

High-dose intravenous immunoglobulins (IVIg) have become a successful new treatment regimen in neurological autoimmune diseases. Most autoimmune disorders are heterogeneous, implicating cellular and humoral immune mechanisms, and this pathogenesis also applies to MS. Many in vivo and in vitro experimental studies have shown that IVIg can therapeutically interfere with the immune system at several levels, but only some are likely to be relevant in MS. Clinical trials of IVIg have investigated the effect on different disease courses and stages of MS. Data show that IVIg have beneficial effects in relapsing-remitting disease, but probably no effect during the secondary progressive phase. IVIg are, therefore, currently considered in some countries as secondline treatments for patients with relapsing-remitting disease when first-line drugs are not tolerated. Despite promising data from animal experiments that IVIg may induce remyelination, human treatment trials have not demonstrated a clinically relevant improvement.

Brain↗
PubMed2004

[Use of i.v. immunoglobulins in neurology. Evidence-based consensus].

Intravenous immunoglobulins (IVIg) have become an alternative immunomodulatory treatment for neurological autoimmune disorders. On the basis of several well conducted placebo-controlled trials evidence is available supporting the efficacy of IVIg. However, of all neurological diseases, IVIg is currently only licensed for Guillain-Barré syndrome. Thus, the off-label use of IVIg has to be focussed although an effective treatment must be made available for the patients, in particular when there is no other treatment alternative. The consensus paper presented here critically discusses the modern studies investigating the use of IVIg in neurological diseases. On the basis of this evidence recommendations for the treatment with IVIg were developed. To achieve a broad and valid consensus, numerous German speaking experts in the field were involved. It is expected that this manuscript will help to ascertain a rational use of IVIg in the future.

Autoimmune Diseases of the Nervous System↗
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2004

Interferon-beta up-regulates the expression of co-stimulatory molecules CD80, CD86 and CD40 on monocytes: significance for treatment of multiple sclerosis.

Interferon (IFN)-beta reduces the biological activity of multiple sclerosis (MS), a presumably T cell-mediated autoimmune disease of central nervous system (CNS) myelin. Co-stimulatory molecules are necessary for full T cell activation and differential expression of co-stimulatory molecules on antigen-presenting cells is thought to influence the type of effector T cell response (Th1/Th2). In this study we investigated the effects of IFN-beta on the expression of co-stimulatory molecules on lymphocytes and monocytes as a potential mechanism of action of IFN-beta in MS. Peripheral blood mononuclear cells (PBMCs) were stimulated with IFN-beta in vitro and expression of CD80, CD86, CD40 and HLA was examined by flow cytometry and reverse-transcription polymerase chain reaction. Whereas IFN-beta had no effect on the expression of these molecules on T and B lymphocytes there was a significant increase on monocytes. Correspondingly, the expression of mRNA increased after 6-18 h. This in vitro response was also observed in untreated MS patients and patients receiving treatment with IFN-beta. The increase of co-stimulatory molecules on monocytes was not mediated by interleukin (IL)-10. When IFN-beta-stimulated monocytes were used to stimulate autologous T cells an increased secretion of IL-13 was observed. In biopsies taken from IFN-beta-induced skin reactions after subcutaneous injection increased expression of CD80 mRNA was detected, indicating that IFN-beta also up-regulates this co-stimulatory molecule in vivo. These data provide the background for further studies of IFN-beta-induced changes of co-stimulatory molecules in MS patients.

Adult↗
PubMed2003

[Chemokine--possible new options for the treatment of multiple sclerosis].

Accumulation and activation of mononuclear cells (lymphocytes and monocytes) in the CNS is one of the crucial steps in the pathogenesis of multiple sclerosis (MS). Chemokines and their receptors govern physiological and pathological leukocyte trafficking and may also be pertinent in hematogenous leukocyte infiltration of the CNS. Due to broad pharmacological interest in the chemokine system, peptide antagonists and small molecular antagonists are now available for clinical therapeutic trials. For the treatment of MS in particular, the chemokine receptors CCR1, CCR2, CCR5, and CXCR3 are possible targets in a chemokine-based therapeutic approach. In this review, we summarize current knowledge of the roles of chemokines and chemokine receptors in the pathogenesis of MS. Furthermore, options for possible therapeutic intervention through the chemokine system are outlined. Clinical studies in MS patients applying this knowledge are expected soon.

Animals↗
PubMed2002

[Intravenous immunoglobulins in multiple sclerosis. Studies and mechanisms of action--an update].

There is no doubt about the immunomodulatory capacity of intravenous immunoglobulins (IVIg). This also holds true for multiple sclerosis (MS), where clinical trials have shown a reduction in relapse rate and number of active lesions on MRI after IVIg treatment. Experimental data in the model of murine Theiler's virus encephalomyelitis (TMEV) gave rise to the hypothesis that IVIg may also promote remyelination. Unfortunately, recent trials were unable to demonstrate clinically relevant remyelination in MS patients treated with IVIg. A possible explanation could lie in the fact that IVIg do not influence the function of oligodendrogilial cells in vitro. In contrast, IVIg can protect oligodendrocytes against complement-mediated injury and thus provide more cells that could engage in remyelination. In addition, IVIg can modulate microglial functions in vitro, thus creating a microenvironment permissive for remyelination. Should such mechanisms also be operative in vivo, they would have escaped detection in the treatment protocols used to date. It would appear that IVIg need to be administered while the inflammatory process is still ongoing, whereas the published trials included only patients with a stable deficit when there is probably little or no active inflammation. Despite new studies on IVIg, its role in the management of MS remains elusive.

Animals↗
PubMed2002

[Transplantation of myelinating cells as regenerative therapy for multiple sclerosis - experimental basis and present state of clinical studies].

Currently available therapies for multiple sclerosis (MS) delay disease progression via immunomodulation or immunosuppression. A persisting neurological deficit is mostly irreversible. Thus, a reparative treatment is urgently warranted. After positive results in animal models, clinical trials to promote endogenous remyelination with intravenous immunoglobulins (IVIg) or the growth factor IGF-1 were performed, unfortunately without clinical improvement. Another possibility to achieve remyelination is the transplantation of myelinating cells into the central nervous system. Proof of principle and demonstration of the functionality were shown in numerous experiments, and a first clinical trial in patients with MS has started. Although there are still several open questions, many are specific to MS and can not be answered in an animal model. This first trial will show if cell transplantation is a feasible concept in MS and whether the transplanted cells will survive and form new myelin. Schwann cells are currently the most promising cells to be transplanted, due to the advantages of an autologous transplantation from the patient's sural nerve biopsy, possibility to expand the cells in culture, and the possibility that they may escape the ongoing inflammatory reaction in MS. Other cell types are available, including stem cells, which are in the centre of a lively discussion. The results of the ongoing trial must be awaited before other transplant studies are performed to tackle other yet unresolved problems. At the time, it seems unlikely that cell transplantation will become clinical practice in the near future.

Animals↗
PubMed2001

Oxides and apoptosis in inflammatory myopathies.

Reactive oxygen intermediates (ROI) and nitric oxide (NO(.)) are produced in abundance in the inflammatory muscle diseases of autoimmune origin polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). However, their role in the pathogenesis of these diseases is so far not clear. In contrast to demyelinating neuropathies, there is no convincing evidence for oxide-induced apoptosis either in myocytes or in lymphocytes and phagocytes in inflammatory myopathies. On the contrary, NO(.) released at low concentrations at target sites may even have cell-protective effects. A major mechanism of protection from apoptosis in both myocytes and inflammatory cells seems to be the upregulation of anti-apoptotic proteins like Bcl-2. Caution is warranted to apply antioxidative and anti-apoptotic agents to patients with inflammatory myopathies as long as the pathogenic role of oxides and apoptosis in the individual case is not resolved.

Animals↗
PubMed2001

Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells.

Chemokines are small proteins that act as chemoattractants and activators in leukocytes during physiological and inflammatory processes. In the CNS chemokine receptors have been shown to be expressed on neurons, astrocytes and microglia but their function in the CNS is poorly understood. CXCR1 and CXCR2 are receptors for ELR-positive CXC chemokines which include growth-regulated oncogene alpha (GRO-alpha) and interleukin-8 (IL-8). GRO-alpha is considered to influence proliferation of cultured oligodendrocyte progenitors (OLPs). Using RT-PCR we show here that the oligodendrocyte precursor cell line CG-4 expresses both CXCR1 and CXCR2. Furthermore we demonstrate that both CG-4 cells and primary cultures of rat OLPs are immunoreactive for CXCR2, the potential receptor for GRO-alpha. This finding demonstrates that the chemokine/chemokine receptor system is probably also involved in the regulation of oligodendroglial cells during developmental processes and may even have implications for inflammatory demyelinating diseases like multiple sclerosis.

Animals↗
PubMed2001

Polyclonal immunoglobulins (IVIg) modulate nitric oxide production and microglial functions in vitro via Fc receptors.

Controlled trials in multiple sclerosis (MS) and case reports in acute demyelinating encephalomyelitis (ADEM) have shown that intravenous immunoglobulins (IVIg) are of therapeutic benefit in central nervous system (CNS) inflammatory diseases. Studies in experimental autoimmune encephalomyelitis (EAE) have suggested these effects are mediated by modulation of the cytokine network and T cell responses. However, there are no data on the influence of IVIg on the local immune reaction in the CNS, the site of inflammation in EAE. We have therefore studied the effect of IVIg on cultured rat microglia, the main immune cell in the CNS. IVIg increased nitric oxide (NO) production in a dose-dependent manner in microglia stimulated with IFNgamma. The increase was only marginal in LPS-treated cells, and no effect was seen in untreated microglia or after stimulation with TNFalpha or PMA. This enhancement of NO production depended on the Fc portion of IVIg and could be abrogated by the pharmacological inhibition of Syk and phosphatidylinositol 3-kinase, two enzymes involved in the signalling cascade of Fc receptors. TNFalpha secretion was dose-dependently stimulated by IVIg in both untreated microglia and after stimulation with LPS or IFNgamma. Again, this effect was mediated through the Fc portion. Finally, we showed that Fc receptor-mediated phagocytosis was inhibited by IVIg, presumably by blockade of the Fc receptor. These different effects may protect oligodendrocytes from antibody mediated phagocytosis and on the other hand could terminate the immune reaction by induction of apoptosis in infiltrating T cells via NO and TNFalpha. We propose that IVIg, in addition to known effects on the peripheral immune system, may also modulate the local immune reaction in CNS inflammatory disease.

Animals↗
PubMed2000

Normal polyclonal immunoglobulins ('IVIg') inhibit microglial phagocytosis in vitro.

Phagocytosis removes pathogens and tissue debris during inflammatory reactions, but also plays an important role in autoimmune reactions. The main phagocytes in the central nervous system (CNS) are microglial cells that are activated during CNS inflammation. In the treatment of inflammatory demyelinating diseases like multiple sclerosis (MS), administration of intravenous immunoglobulins (IVIg) has become a promising immunomodulatory therapy. Although a large number of potential mechanisms for the effects of IVIg has been suggested, the precise mode of action in CNS inflammation is unknown. We assessed the influence of IVIg on phagocytosis and endocytosis in microglia in vitro. IVIg had little effect on non-specific phagocytosis of latex particles in untreated microglia, while there was a dose-dependent inhibition in microglia activated with LPS and IFNgamma. Endocytosis of soluble myelin basic protein (MBP) was downregulated by IVIg in both untreated and activated microglia. The effect was mediated by an F(ab')(2) preparation of immunoglobulins, suggesting that Fc receptor-mediated phagocytosis is not involved. Intact IVIg, but not F(ab')(2) fragments also suppressed Fc receptor-mediated phagocytosis of opsonised erythrocytes in both untreated and activated microglia. These results show that IVIg can inhibit the phagocytic activity of microglia via different mechanisms. Such an effect could contribute to the immunomodulatory capacity of IVIg in inflammatory CNS diseases.

Animals↗