Multiple Sclerosis: Toyka KV

Anonymous00013, Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. · Department of Neurology and Clinical Research, Unit for MS and Neuroimmunology, University of Würzburg, Würzburg, Germany. · J Neurol. · Pubmed #19005625 No free full text.

Abstract: This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

Rieckmann P, Toyka KV. · Klinische Forschungsgruppe für Multiple Sklerose und Neuroimmunologie, Neurologische Universitätsklinik, Würzburg, Deutschland. · Eur Neurol. · Pubmed #10529535 No free full text.

Abstract: The promising results of several multicenter studies during the last few years have improved the immunomodulatory treatment of multiple sclerosis (MS). The different compounds tested were shown to reduce the number of relapses and to modulate the course of disease to various extents. The transition of the results obtained in therapeutic trials into daily clinical practice is often delayed or even hampered by monetary restrictions or reluctance of the medical community to adjust their approach to new treatments. After an initial inquiry had shown that less than 50% of eligible patients received any active immunomodulating treatment, a consensus group of Austrian, German and Swiss MS societies was formed in order to prepare a report of the current treatment options in MS. The aim of this report is to present the consensus on a new concept of escalating immunotherapy in MS. Future updates of the report are planned on a yearly basis or whenever substantial new evidence becomes available.

Henze T, Toyka KV. · No affiliation provided · Nervenarzt. · Pubmed #15480525 No free full text.

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Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Götschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freimüller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Brück W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, Jügelt E, Koehler J, Kölmel W, König N, Lowitzsch K, Manegold U, Melms A, Mertin J, Oschmann P, Petereit HF, Pette M, Pöhlau D, Pohl D, Poser S, Sailer M, Schmidt S, Schock G, Schulz M, Schwarz S, Seidel D, Sommer N, Stangel M, Stark E, Steinbrecher A, Tumani H, Voltz R, Weber F, Weinrich W, Weissert R, Wiendl H, Wiethölter H, Wildemann U, Zettl UK, Zipp F, Zschenderlein R, Izquierdo G, Kirjazovas A, Packauskas L, Miller D, Koncan Vracko B, Millers A, Orologas A, Panellus M, Sindic CJ, Bratic M, Svraka A, Vella NR, Stelmasiak Z, Selmaj K, Bartosik-Psujik H, Mitosek-Szewczyk K, Belniak E, Mochecka A, Bayas A, Chan A, Flachenecker P, Gold R, Kallmann B, Leussink V, Mäurer M, Ruprecht K, Stoll G, Weilbach FX, Anonymous00046. · Dept. of Neurology, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. · J Neurol. · Pubmed #15592728 No free full text.

Abstract: 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.

Wolinsky JS, Toyka KV, Kappos L, Grossberg SE. · No affiliation provided · Lancet Neurol. · Pubmed #12941572 No free full text.

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Gold R, Dalakas MC, Toyka KV. · Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany. <> · Lancet Neurol. · Pubmed #12849298 No free full text.

Abstract: Important progress has been made in our understanding of the cellular and molecular processes underlying autoimmune neuromuscular diseases that has led us to identify targets for rational therapeutic intervention. Although antigen-specific immunotherapy is not yet available, old and new immunomodulatory treatments, alone or in combination, provide effective immunotherapy for most autoimmune disorders. In parallel, the achievements of molecular medicine provide more specific yet largely experimental therapeutic tools that need to be tested in the human diseases. Here we review the principles and targets of immunotherapy for autoimmune neuromuscular disorders, address applications and practical guidelines, and give an outlook on future developments.

Toyka KV, Gold R. · Department of Neurology, Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians University, Würzburg, Germany. · Neurology. · Pubmed #12707416 No free full text.

Abstract: Current knowledge about the pathogenic mechanisms involved in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) supports an autoimmune etiology. Some of the cell and humorally mediated immune responses that contribute to the development of CIDP resemble those implicated in multiple sclerosis (MS). The effector role of circulating antibodies has recently been revisited. In addition, similar to the situation in MS, histopathologic studies support the heterogeneity of disease mechanisms in CIDP, with variants showing axon damage. In addition to intravenous immunoglobulin (IVIg), prednisone, and plasma exchange, immunomodulatory drugs also were used to treat CIDP, although no definitive trial data are available. One class of immunomodulators, interferon beta formulations, has proven efficacy in the treatment of MS, and because of clinical similarities between the two diseases it is attractive to investigate whether some agents that are effective in the treatment of MS would also be effective in CIDP. Preliminary studies have evaluated the effects of interferon beta formulations in the treatment of CIDP, one of which has shown promising results and warrants further investigation.

Mäurer M, Toyka KV, Gold R. · Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians-Universität Würzburg, Germany. · Rev Neurol (Paris). · Pubmed #12690655 No free full text.

Abstract: Autoimmune demyelinating neuropathies, like Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), are characterized by local inflammation and demyelination of peripheral nerves. The therapeutic response to plasma exchange and IVIg points to an important role for humoral factors in the pathogenesis of these autoimmune disorders of the peripheral nervous system (PNS). The similarity of the human disease with its animal model disease experimental autoimmune neuritis (EAN), and the activation of T-cell and macrophage derived cytokines all indicate that cellular immunity is also of relevance. Many of the basic principles in autoimmune inflammatory neuropathies have been learned from studies in EAN which can now be linked to the human disorders. This article summarizes current aspects of cellular immunity in autoimmune demyelinating disorders of the PNS. Better understanding of these cellular immunoregulatory mechanisms may help to develop new therapeutic strategies.

Rieckmann P, Toyka KV, Anonymous00266. · Neurologische Klinik, Julius-Maximilians-Universität, Josef-Schneider-Strasse 11, 97080 Würzburg. · Nervenarzt. · Pubmed #12243005 No free full text.

Abstract: This update of the consensus on escalating immunotherapy in multiple sclerosis includes for the first time also important aspects of diagnosis, documentation, and cost of disease. The application of evidence-based therapeutic recommendations as described in the first two publications of the MSTKG has already improved the treatment situation for MS patients. It appears that the positive attitude towards a more active immunomodulatory therapy also helped to improve MS therapy in general. Due to the increasing use of standardized clinical documentation, individual recommendations for the application of innovative products are now clearer for patients as well as health care providers. The study on the cost of MS performed in several European countries demonstrated that medical treatment constitutes only a small part of the total cost of MS. It was demonstrated that MS-related costs correlate almost exponentially with increasing disability. Therefore, pharmacoeconomic reasons might also speak for early, individually adjusted, and escalating immunotherapy. This would also include a stringent therapy of individual relapses aimed at a complete resolution of clinical symptoms. Recent studies focus on a possible dose-effect relation for recombinant beta-interferons. The available data suggest a possible relation, but they have to be interpreted with caution, as important issues in the design of the studies (e.g., maintenance of blinding) were not adequately addressed. Up to now, there has been no general recommendation for a differential indication of the individual licensed substances, but the different available dose regimes and modes of application allow for an individual adjustment of therapy. In addition to immunomodulatory treatment, vaccinations and their effect on the disease course are important aspects in patient care. According to recent large epidemiological studies, the recommendations have changed as the relevant immunizations with split vaccines (e.g., influenza, tetanus) are now regarded as safe and without increased risk of relapse or disease progression.

Magnus T, Chan A, Savill J, Toyka KV, Gold R. · Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians-University, D-97080, Würzburg, Germany. · J Neuroimmunol. · Pubmed #12225883 No free full text.

Abstract: Apoptotic cell death of inflammatory T cells is an established mechanism to terminate an autoimmune inflammatory response in the rodent and human central nervous system (CNS). The efficient clearance of apoptotic cells protects the tissue from leakage of potentially harmful substances from secondary necrotic cells. As the resident phagocyte, the microglial cell is the primary candidate for the clearance of apoptotic lymphocytes. Furthermore, the phagocytosis of apoptotic cells is accompanied by a spectrum of anti-inflammatory effects. In this review, we focus on the mechanisms for removal of apoptotic inflammatory cells by microglia in the central nervous system and their functional consequences.

Bayas A, Hummel V, Kallmann BA, Karch C, Toyka KV, Rieckmann P. · Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Department of Neurology, University of Würzburg, Germany. · Cytokine. · Pubmed #12182839 No free full text.

Abstract: Inflammatory stimuli within the central nervous system may not only induce tissue damage but may also convey neuroprotection. It has been shown that brain derived neurotrophic factor (BDNF) is a neuroprotective candidate. Here we show that BDNF is constitutively expressed in cultured human cerebral endothelial cells (HCEC) and can further be upregulated under proinflammatory conditions. TNF-alpha treatment resulted in an increase in BDNF mRNA expression and protein levels were significantly elevated after 72 h (69+/-33%, P<0.01). Using functional assays it was demonstrated that BDNF produced by HCEC is bioactive and supports motoneuron survival. In contrast, BDNF expression was reduced by TNF-alpha in human umbilical vein endothelial cells (HUVEC). We conclude that HCEC likely to contribute to neuronal survival under physiological and inflammatory conditions.

Grauer O, Offenhäusser M, Schmidt J, Toyka KV, Gold R. · Klinische Forschungsgruppe für Multiple Sklerose und Neuroimmunologie, Neurologische Klinik und Poliklinik, Julius-Maximilians-Universität, Würzburg. · Nervenarzt. · Pubmed #11519198 No free full text.

Abstract: High-dose intravenous glucocorticosteroids (GS) are the treatment of choice for acute relapses in patients with multiple sclerosis. We review the evidence from published trials on GS treatment in MS. Several controlled clinical trials have proven the efficacy of high-dose GS in accelerating the recovery from acute attacks. With serial MRI recordings, a reduction in the number of enhancing lesions has been observed after high-dose GS treatment. Definitive long-term effects of GS on disease evolution could not been demonstrated. There is now evidence that ultra-high doses of GS might be superior in comparison to standard pulse treatment regarding relapse rate and disease progression. In experimental autoimmune encephalomyelitis (EAE), an animal model for some features of MS, doses of up to 50 mg/kg methylprednisolone markedly augmented T cell apoptosis in situ, leading to a faster clearance of inflammatory infiltrates. Apoptosis in peripheral blood leukocytes could also be detected after i.v. GS treatment in MS patients. In a recent MRI study, ultra-high doses of GS were significantly more effective in reducing contrast-enhancing lesions and in maintaining blood-brain barrier integrity after a clinical relapse. Further clinical trials are necessary to study the long-term effects of ultra-high doses of GS on disease progression and disability.

Gold R, Buttgereit F, Toyka KV. · Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Department of Neurology, Julius Maximilians Universität Würzburg, Germany. · J Neuroimmunol. · Pubmed #11430999 No free full text.

Abstract: Glucocorticosteroids are the most potent immunosuppressive and antiinflammatory drugs. Over the six decades that have passed since their discovery, a variety of genomic effector mechanisms of steroid hormones has been described which are mediated by the cytosolic steroid receptor. Recent evidence supports a direct effect of glucocorticosteroids on cellular membranes that occurs at higher hormone concentrations, termed nongenomic effects. These imply a qualitatively distinct mode of steroid action leading to cellular apoptosis. In this review, we discuss in vitro and in vivo data on nongenomic effects of glucocorticosteroids and their possible implications for the therapy of human neuroimmunological diseases.

Flachenecker P, Toyka KV. · Neurologischen Klinik und Poliklinik, Universität Würzburg. · Versicherungsmedizin. · Pubmed #10992796 No free full text.

Abstract: The diagnosis of multiple sclerosis is primarily based on clinical criteria considering the dissemination of neurological symptoms in time and space. Laboratory tests (magnetic resonance imaging, examination of cerebrospinal fluid, and evoked potentials) are important to confirm the diagnosis and assess disease activity. With the improvement of these methods, MS could be diagnosed at a very early stage of the disease allowing for the prompt initiation of immunotherapies. An early diagnosis and prediction of the future course of MS are also important for adequate counselling of the predominantly young patients about their professional plans. However, in the early stages of MS, prediction of disability remains difficult even if the patient is definitely diagnosed to suffer from MS.

Gold R, Hartung HP, Toyka KV. · Department of Neurology, University of Wurzburg, Neurologische Universitätsklinik, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. · Mol Med Today. · Pubmed #10652482 No free full text.

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that takes a relapsing-remitting or a progressive course (reviewed in Refs 1,2). Its counterpart in the peripheral nervous system (PNS) is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (reviewed in Ref. 3). In addition, there are acute, monophasic disorders, such as the inflammatory demyelinating polyradiculoneuropathy termed Guillain-Barré syndrome (GBS) in the PNS, and acute disseminated encephalomyelitis (ADEM) in the CNS. Both MS and GBS are heterogeneous syndromes. In MS different exogenous assaults together with genetic factors can result in a disease course that finally fulfils the diagnostic criteria. In both diseases, axonal damage can add to a primarily demyelinating lesion and cause permanent neurological deficits. No single animal model exists that mimics all the features of human demyelinating diseases; rather, the available models reflect specific facets. Here, we focus on experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN) as models in rat and mouse strains, and discuss their distinct histopathology and the roles played by different autoantigens.

Cursiefen S, Flachenecker P, Rieckmann P, Toyka KV. · Neurologische Klinik und Poliklinik, Julius-Maximilians-Universität, Würzburg. · Nervenarzt. · Pubmed #10483572 No free full text.

Abstract: Mitoxantrone is an anthracenedione anti-neoplastic agent that has recently been shown to be effective in ameliorating disease activity in multiple sclerosis (MS) as indicated by clinical and MRI data. However, the role of mitoxantrone in escalating treatment of patients with frequent and severe relapses and with rapid progression of disability is less clear. In this retrospective analysis we report on 15 patients with severe relapsing-remitting (9 patients) and secondary progressive MS with superimposed exacerbations (6 patients) treated open-labeled with mitoxantrone in our Clinical Research Group from July 1994 to October 1998. Eleven of these patients (73%) were treated with azathioprine, interferon-beta-1b or cyclophosphamide before. The patients received mitoxantrone over a period of at least 12 months (19 +/- 6 months) with a single dose of 10 mg/m2 monthly for the first three months. Thereafter, infusions were repeated every 3 months (total dose 141 mg +/- 45 mg). The annual relapse rate could be significantly reduced from 3.0 +/- 1.5 in the year before therapy to 0.5 +/- 0.5 during therapy. Nine patients (60%) were stabilised, while four patients (27%) showed an improvement of disability. The treatment was well tolerated with only minor side effects. These results although retrospectively obtained confirm previous trials showing that mitoxantrone may be useful in MS patients with frequent and severe exacerbations and/or a rapidly progressive course of the disease who have had other immunomodulatory medication.

Stangel M, Toyka KV, Gold R. · MRC Centre for Brain Repair, Cambridge University, England. · Arch Neurol. · Pubmed #10369303 links to  free full text

Abstract: Administration of high-dose intravenous immunoglobulins has become one of the most successful new treatment regimens for demyelinating diseases. In a decade of molecular medicine, it came as a surprise that a natural blood product would prove effective in several disorders, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and, probably, multiple sclerosis. Many experimental studies, both in vivo and in vitro, have shown that intravenous immunoglobulins can interfere with the immune system at several levels. In addition, intravenous immunoglobulins may promote remyelination in demyelinating disease associated with viral infections. At present, no single mode of action has been identified as the crucial mechanism, which leads us to suggest that multiple effects may act in concert.

Henze T, Rieckmann P, Toyka KV, Anonymous00094. · Reha-Zentrum Nittenau, Rehabilitationszentrum fur Neurologie, Nittenau, Germany. · Eur Neurol. · Pubmed #16966832 No free full text.

Abstract: Besides immunomodulation and immunosuppression, the specific treatment of symptoms is an essential component of the overall management of multiple sclerosis (MS). Symptomatic treatment is aimed at the elimination or reduction of symptoms impairing the functional abilities and quality of life of the affected patients. Moreover, with symptomatic treatment the development of a secondary physical impairment due to an existing one may be avoided. Many therapeutic techniques as well as different drugs are used for the treatment of MS symptoms, but only a few of them have been investigated, especially in MS patients, and are approved by the national health authorities. Despite an overwhelming number of publications, only a few evidence-based studies exist and consensus reports are very rare, too. Therefore, it seemed necessary to develop a consensus statement on symptomatic treatment of MS comprising existing evidence-based literature as well as therapeutic experience of neurologists who have dealt with these problems over a long time. This consensus paper contains proposals for the treatment of the most common MS symptoms: disorders of motor function and coordination, of cranial nerve function, of autonomic, cognitive, and psychological functions as well as MS-related pain syndromes and epileptic seizures.

Rieckmann P, Kruse N, Nagelkerken L, Beckmann K, Miller D, Polman C, Dahlke F, Toyka KV, Hartung HP, Stürzebecher S. · Neurologische Universitätsklinik Würzburg, Würzburg, Germany. · J Neurol. · Pubmed #15895275 No free full text.

Abstract: BACKGROUND : Subcutaneous IFNbeta-1b (Betaferon) is an established immunomodulatory treatment for relapsing remitting MS and active secondary progressive multiple sclerosis (SPMS). It modulates cytokine and adhesion molecule expression but long term in vivo effects of IFNbeta-1b on the immune system are not known in multiple sclerosis. OBJECTIVE : To address the effects of IFNbeta-1b on serum levels for soluble adhesion molecules and cytokine receptors from MS patients. METHODS : Serial blood samples were obtained from 40 patients of the frequent MRI subgroup (20 patients each from the placebo and the IFNbeta-1b treatment group), participating in the European multi-center clinical trial with IFNbeta-1b for secondary progressive MS, at regular intervals for up to 36 months. Soluble adhesion molecules (sVCAM, sICAM-1, sL-Selectin) as well as TNF-receptor I and II were analysed in the serum of patients by enzyme linked immunosorbent assays (ELISAs). Monthly brain MRI was performed in 34 of these patients (16 patients from the placebo and 18 from the IFNbeta-1b group) during months 1-6 and 19-24 to monitor disease activity as assessed by newly occurring gadolinium (Gd) enhancing lesions. RESULTS : An early and significant increase in sVCAM and sTNF-RII serum levels was detected in 16 out of 20 patients (80 %) treated with subcutaneous IFNbeta-1b already at month 1 but was absent in all but one patient during placebo treatment (p < 0.01). Raised sVCAM and TNF RII serum levels during months 1-6 inversely correlated with less MRI activity in the 19-24 months treatment interval in the IFNa-1b treatment group ( p = 0.0093 for TNF-RII; p = 0.047 for VCAM). CONCLUSIONS : sVCAM and sTNF RII levels in the serum of SPMS patients are increased during IFNbeta-1b therapy and may at least in part explain some of the treatment effects, like reduced immune cell transmigration.

Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV. · Department of Neurology, Julius-Maximilians-Universität Würzburg, Germany. · Mult Scler. · Pubmed #11724449 No free full text.

Abstract: BACKGROUND: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. OBJECTIVES: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. METHODS: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0 +/- 7.3 years, and nine patients with clinically stable MS, age 41.3 +/- 10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-beta-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. RESULTS: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the 'active' patient group (39%) than in healthy controls (8%, P< 0.02) or 'stable' patients (0%, P< 0.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in 'active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P<0.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P<0.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P<0.002). No difference was seen for any of the autonomic scores between patients treated with interferon-beta (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. CONCLUSIONS: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.

Stenner MP, Waschbisch A, Buck D, Doerck S, Einsele H, Toyka KV, Wiendl H. · Department of Neurology, Julius-Maximilians University, Wuerzburg, Germany. · PLoS One. · Pubmed #18836525 links to  free full text

Abstract: BACKGROUND: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients. METHODOLOGY: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs. PRINCIPAL FINDINGS: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment. CONCLUSIONS: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

Hofstetter HH, Grau C, Buttmann M, Forsthuber TG, Gaupp S, Toyka KV, Gold R. · Clinical Research Group for Multiple Sclerosis, Department of Neurology, University of Würzburg, Würzburg, Germany. · Cytokine. · Pubmed #17881243 No free full text.

Abstract: Experimental autoimmune encephalomyelitis (EAE) is commonly regarded as an animal model of the human disease multiple sclerosis (MS). Pertussis toxin (PTX) is routinely used for EAE induction in mice. Besides opening the blood-brain barrier, it acts as an adjuvant causing strong expansion of antigen-specific cells after coinjection with neuroantigens in IFA. Using an IL-17 ELISPOT assay we developed previously, we investigated the capability of PTX to induce proteolipid protein peptide 139-151(PLPp)-specific Th-17 cells in the immune periphery and in the thymus after coinjection with PLPp/IFA. PTX was found to induce peripheral PLPp-specific Th-17 cells in the draining lymph node and in the spleen, but not in the thymus. Our study indicates a new mechanism by which microbial agents can initiate or maintain autoimmune reactions and supports the growing role in particular for Th-17 cells in organ-specific autoimmune diseases like multiple sclerosis or EAE.

Tischner D, Weishaupt A, van den Brandt J, Müller N, Beyersdorf N, Ip CW, Toyka KV, Hünig T, Gold R, Kerkau T, Reichardt HM. · Institute for Virology and Immunobiology, University of Würzburg, Germany. · Brain. · Pubmed #16921176 links to  free full text

Abstract: Recruitment of naturally occurring CD4+ CD25+ regulatory T (T(reg)) cells is a highly promising approach for the treatment of experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis. Here, we studied the in vivo interaction of T(reg) cells, induced by the monoclonal anti-CD28 antibody JJ316, with encephalitogenic T cell lines established from eGFP-transgenic rats. By tracking these fluorescent cells using flow cytometry and confocal microscopy, we found that the activation and expansion of T(reg) cells inhibited infiltration of the CNS by pathogenic T cells. Interference with effector cell migration occured within the secondary lymphoid organs, since the early therapeutic effects were achieved despite the absence of T(reg) cells in the spinal cord. However, the delayed homing to the CNS seen after prophylactic JJ316 administration indicates that T(reg) cells may play an additional role within the target tissue. In addition, the blood-brain barrier remained largely intact after JJ316 treatment, the secretion of T(H)2 cytokines was augmented and the encephalitogenic T cells exhibited a reduced secretion of IFN-gamma. This in turn resulted in a reduced expression of the chemokine receptor CXCR-3 on effector T cells which may interfere with their capacity to infiltrate the CNS. Importantly, these effects were not achieved by direct action of JJ316 on the encephalitogenic cells. Our data rather suggest that polyclonal activation of T(reg) cells in the secondary lymphoid organs is instrumental in preventing the pathological transmigration of encephalitogenic T cells into the CNS. We anticipate that these results may help to better understand the role of T(reg) cells in controlling autoimmunity in the CNS.

Hofstetter HH, Lühder F, Toyka KV, Gold R. · Clinical Research Group for Multiple Sclerosis, Department of Neurology, University of Würzburg, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany. · Cytokine. · Pubmed #16815032 No free full text.

Abstract: IL-17 is a potent proinflammatory cytokine produced by activated memory T cells. Recent studies in both human autoimmune diseases and in their animal models have indicated that IL-17 rather than IFN-gamma might be the essential T-cell effector cytokine in the T-cell mediated autoimmune process. Since the thymus has a central role in maintaining T-cell self-tolerance and disturbance of thymic self-tolerance is implied in various autoimmune diseases, we here investigated the capability of murine thymocytes to produce IL-17. Our results indicate that thymocytes are a potent source of IL-17 in response to CD3 stimulation and various microbial immune stimuli and thereby show different patterns in the expression of the proinflammatory cytokines IFN-gamma and IL-17. In addition, strong differences between thymocytes and splenocytes were detected. Altered IL-17 production by thymocytes upon contact with foreign pathogens might be a key regulator in the education of adaptive immunity.

Stasiolek M, Bayas A, Kruse N, Wieczarkowiecz A, Toyka KV, Gold R, Selmaj K. · Department of Neurology, Medical University of Lodz, Lodz, Poland. · Brain. · Pubmed #16513684 links to  free full text

Abstract: Plasmacytoid dendritic cells (pDCs) represent a DC subtype that exerts divergent functions in innate and adoptive immunity including the immediate reaction to microbial factors and the induction of immunoregulatory responses. It is thought that different DC subtypes may be critically involved in the pathogenesis of multiple sclerosis (MS). In our study we assessed the phenotype, maturation and functional properties of peripheral blood pDCs from 35 clinically stable, untreated multiple sclerosis patients, 30 healthy controls and 9 patients with pneumonia, which was used as a non-specific inflammatory condition (NIC). Ex vivo expression of CD86 and 4-1BBL was significantly lower on pDCs from multiple sclerosis patients than from controls and patients with NIC (22 versus 47 versus 41% and 12 versus 35 versus 32%, respectively). When stimulated with IL-3 and CD40L, pDCs of multiple sclerosis patients showed inefficient maturation as demonstrated by significantly lower or delayed upregulation of CD86, 4-1BBL, CD40 and CD83. Additionally, in multiple sclerosis, stimulation of pDCs by unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) resulted in a significantly lower interferon (IFN) alpha secretion than in controls. In multiple sclerosis, but not in controls, pDCs failed to upregulate proliferative responses and IFN-gamma secretion of autologous peripheral blood mononuclear cells (PBMC) in a co-culture system. Moreover, depletion of pDCs in multiple sclerosis patients, but not in controls, had no effect on generation of CD4+Foxp3+ regulatory T cells. We also provide data showing that glatiramer acetate (GA) treatment partially restores phenotype and function of pDCs in multiple sclerosis patients. These findings suggest functional abnormalities of pDCs in these patients, which might be of importance in the understanding of the development of immune dysregulation in this disease.