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Ralf Gold

Publications and source records attributed to Ralf Gold.

At least 19 recordsLinked to original sources
PubMed2007

Antigen therapy of experimental autoimmune encephalomyelitis selectively induces apoptosis of pathogenic T cells.

Administration of high-dose myelin antigen induces massive T cell apoptosis in experimental autoimmune encephalomyelitis (EAE) but the nature of the target cells remains elusive. Here we have used a cell line established in eGFP-transgenic Lewis rats to distinguish between pathogenic and bystander T cells in adoptive transfer EAE. Intravenous application of gpMBP strongly reduced the amount of encephalitogenic cells in spinal cord and spleen while the number of the other T cells remained constant. This could be attributed to their differential sensitivity to apoptosis. Thus, antigen therapy selectively targets pathogenic T cells and should therefore limit potential adverse effects.

Adoptive Transfer↗
PubMed2007

Drug Insight: the use of intravenous immunoglobulin in neurology--therapeutic considerations and practical issues.

Over the past few years, we have achieved increasing success in the treatment of a number of autoimmune-mediated disorders affecting nerves and muscles. This success is partly attributable to the use of high-dose polyclonal intravenous immunoglobulin (IVIg), which has dramatically changed our treatment options. On the basis of results from controlled, but non-FDA-approved, clinical trials, IVIg is now the treatment of choice for Guillain-Barré syndrome, chronic idiopathic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy; IVIg offers rescue therapy for patients with rapidly worsening myasthenia gravis, and is a second-line therapy for dermatomyositis, stiff-person syndrome, and pregnancy-associated or postpartum multiple sclerosis attacks. The ability of IVIg to treat such immunologically diverse disorders effectively, coupled with its excellent safety profile, has led clinicians to use the drug more liberally, even in diseases for which the data are weak and not evidence-based and in patients with coexisting conditions. Use of IVIg for such indications can increase the risk of complications while raising the cost of the drug. Practical issues regarding dosing and frequency of infusions generate dilemmas in clinical practice. In this article, we review the current indications for IVIg treatment, address practical issues related to the use and costs of the drug, and summarize its mechanisms of action.

Autoimmune Diseases↗
PubMed2007

Downregulation of transforming growth factor-beta2 facilitates inflammation in the central nervous system by reciprocal astrocyte/microglia interactions.

The central nervous system is an immune privileged organ in which inflammatory reactions are normally downregulated by mechanisms that are not completely understood. Transforming growth factor (TGF)-beta2 is constitutively expressed in the adult central nervous system and little is known about its regulation and modulatory role during neuroinflammation. In this study, we show that TGFbeta2 mRNA and protein are downregulated in the acute phase of chronic relapsing experimental autoimmune encephalomyelitis, whereas the homologous cytokine TGFbeta1 is upregulated. To further characterize regulatory mechanisms, we resorted to an in vitro glial cell culture system. The proinflammatory cytokines IFNgamma and TNFalpha suppressed TGFbeta2 secretion by astrocytes, the major intracerebral producers of TGFbeta2. On the cellular level, activated microglia inhibited TGFbeta2 secretion but induced TGFbeta1 through soluble factors. On the other hand, TGFbeta2 influenced antigen-presenting cell functions of microglia by downregulating major histocompatibility complex class II expression and costimulatory/adhesion molecules, and thereby inhibited myelin basic protein-specific T cell proliferation. These data suggest that TGFbeta2 plays a central role in maintenance of the immune privilege of the central nervous system. Downregulation of astrocytic TGFbeta2 by T cell- and microglia-secreted cytokines appears to be a critical step in providing the grounds for acute and chronic neuroinflammation.

Animals↗
PubMed2006

Error processing in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a genetic disorder expressed by a degeneration of the basal ganglia inter alia accompanied with dopaminergic alterations. These dopaminergic alterations are related to genetic factors i.e., CAG-repeat expansion. The error (related) negativity (Ne/ERN), a cognitive event-related potential related to performance monitoring, is generated in the anterior cingulate cortex (ACC) and supposed to depend on the dopaminergic system. The Ne is reduced in Parkinson's Disease (PD). Due to a dopaminergic deficit in HD, a reduction of the Ne is also likely. Furthermore it is assumed that movement dysfunction emerges as a consequence of dysfunctional error-feedback processing. Since dopaminergic alterations are related to the CAG-repeat, a Ne reduction may furthermore also be related to the genetic disease load. METHODOLOGY/PRINCIPLE FINDINGS: We assessed the error negativity (Ne) in a speeded reaction task under consideration of the underlying genetic abnormalities. HD patients showed a specific reduction in the Ne, which suggests impaired error processing in these patients. Furthermore, the Ne was closely related to CAG-repeat expansion. CONCLUSIONS/SIGNIFICANCE: The reduction of the Ne is likely to be an effect of the dopaminergic pathology. The result resembles findings in Parkinson's Disease. As such the Ne might be a measure for the integrity of striatal dopaminergic output function. The relation to the CAG-repeat expansion indicates that the Ne could serve as a gene-associated "cognitive" biomarker in HD.

Adult↗
PubMed2006

Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells.

Apoptosis of autoaggressive T cells in the central nervous system (CNS) and subsequent phagocytosis by microglia is probably crucial in the rapid resolution of the inflammatory infiltrate in T cell mediated neuroinflammatory diseases. In addition to mere clearance, phagocytosis of apoptotic leukocytes results in the downregulation of different microglial immune functions. Chemoattractive functions of Lewis rat microglia and secretion of chemokines and matrix-metalloproteinases (MMPs) were investigated after phagocytosis of apoptotic T cells in vitro. In a modified Boyden chamber assay migration of encephalitogenic T cells toward LPS-stimulated microglial supernatants after phagocytosis of apoptotic thymocytes was reduced by 24.9% in comparison to interaction with viable target cells (P < 0.001). Phagocytosis of apoptotic cells downregulated CC-chemokine ligand (CCL)-5-secretion by LPS-stimulated microglia by 66.2% (P < 0.001), whereas there was only a trend toward decreased CCL2-secretion. As determined by gelatinase-zymography, secretion of MMP-9 by microglia was decreased after phagocytosis of apoptotic cells, whereas MMP-2 secretion was not altered. These mechanisms may reduce further recruitment of pathogenic inflammatory cells into the CNS-lesion and thus contribute to the active resolution of the inflammatory infiltrate and termination of the autoimmune attack.

Animals↗
PubMed2006

Differential expression of BDNF mRNA splice variants in mouse brain and immune cells.

For the neurotrophin BDNF several splice variants were recently described. We analyzed the expression of mBDNF mRNA splice variants in cells of the immune system in comparison to the central nervous system (CNS). Whereas all splice variants are expressed in the CNS, only mBDNF 3 mRNA could be detected in primary and secondary lymphoid organs as well as in purified T cells and macrophages. After activation, only mBDNF 3 mRNA expression was upregulated in T cells without the additional appearance of other mBDNF splice variants. Therefore, mBDNF mRNA is differentially regulated in the CNS and the immune system opening the possibility of specific manipulation of mBDNF expression in immune cells without globally affecting mBDNF in the CNS.

Animals↗
PubMed2006

Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis.

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.

Animals↗
PubMed2006

IL-17 production by thymocytes upon CD3 stimulation and costimulation with microbial factors.

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.

Animals↗
PubMed2006

Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.

In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.

Animals↗
PubMed2006

Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis.

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.

Antigens, CD↗
PubMed2006

Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes.

We have used the 5' flanking sequence of the myelin basic protein gene known to include the core promoter and a strong oligodendrocyte (ODC)-specific enhancer to target expression of the well-studied model antigen ovalbumin (OVA) to ODC in transgenic mice. OVA protein was detected in a tissue- and cell-specific manner in these "ODC-OVA" mice. Without immunization, CD4 T cells and B cells remained ignorant of the neo-self antigen expressed in the central nervous system (CNS), as indicated by unimpaired development and lack of activation of OVA/IA(b)-specific TCR transgenic T cells in these mice, and the ability to mount normal OVA-specific recall and antibody responses. Upon immunization with OVA in complete Freund's adjuvant, about half of the transgenic mice developed neurological symptoms characteristic of experimental autoimmune encephalomyelitis (EAE). Mononuclear infiltrates in the brain and spinal cord contained both macrophages and T cells, similar to classical models of EAE induced by immunization with CNS antigens in adjuvant. The wealth of immunological reagents available to study and manipulate the OVA-specific response should make this new model useful for the investigation of components and mechanisms involved in CNS-specific autoimmunity.

Animals↗
PubMed2006

Mycophenolate mofetil and tacrolimus: new therapeutic options in neuroimmunological diseases.

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.

Autoimmune Diseases of the Nervous System↗
PubMed2006

Therapy of immune neuropathies with intravenous immunoglobulins.

Autoimmune-mediated disorders belong to the main causes of neuropathies worldwide. During recent years much progress has been achieved in the understanding of the underlying pathomechanisms, associated with implications for therapeutic approaches. Here we will briefly review the pathogenesis and discuss treatment options of the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and neuropathies associated with paraproteinemias. In most of these disease entities intravenous immunoglobulins play a major role as effective and safe treatment options.

Guillain-Barre Syndrome↗
PubMed2006

Anti-GT1a IgG antibodies in a child with severe Guillain-Barré syndrome.

This report describes a male, age 8 years 10 months, with severe Guillain-Barré syndrome after Campylobacter jejuni infection. The patient developed fulminant muscle weakness, external ophthalmoplegia, bulbar palsy, and respiratory distress. A high level of serum monospecific anti-GT1a immunoglobulin G antibody was detected. He was treated with intravenous immunoglobulins and artificial ventilation. Two years after the onset, the patient still suffered from residual leg weakness and foot drop. After 3 years and clinical recovery, the antibody was no longer detectable. This report presents the first case in childhood suggesting an association between a severe Guillain-Barré syndrome after C. jejuni enteritis with monospecific anti-GT1a immunoglobulin G antibody.

Antibodies, Anti-Idiotypic↗
PubMed2006

Glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis.

Glucocorticoids exert a variety of immunomodulatory activities. Since changes in glucocorticoid homeostasis impact on susceptibility to autoimmune diseases, and synthetic glucocorticoids are widely used in the treatment of multiple sclerosis, a detailed understanding of their mechanism of action is desirable. Experimental autoimmune encephalomyelitis is a common animal model that mirrors many hallmarks of multiple sclerosis, a chronic inflammatory disease of the CNS with presumed autoimmune origin. Experimental autoimmune encephalomyelitis has been instrumental for many years in studying multiple sclerosis, revealing the blood-brain barrier, the microglia and T-cell apoptosis as major targets of glucocorticoids in this disease. Despite the great advances in the field, the answers to many questions concerning the mechanism of glucocorticoids; for example, the contribution of nongenomic effects or the cell-type specificity of their action, remain elusive. This review will critically discuss what we have learned so far from the analysis of animal models of the molecular mode of therapeutic and endogenous glucocorticoid action in multiple sclerosis. With this knowledge in mind, we should be able to further improve the management of multiple sclerosis using this class of drugs.

Animals↗