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Ralf Gold

Publications and source records attributed to Ralf Gold.

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

Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is widely regarded as an animal model of the human disease multiple sclerosis. A multitude of studies has investigated the neuroantigen-specific T-cell mediated cytokine pattern present in animals with EAE. In particular, the role of the so-called Th1- and Th2-cytokines has been addressed. In a recent study, it has been demonstrated that IL-23 rather than IL-12 is critical for modulating the character of the developing immune response towards a proinflammatory response and leading to EAE. IL-17 is a crucial effector cytokine, whose production is specifically triggered by IL-23, and it has been shown to be an essential inflammatory mediator in other autoimmune diseases and inflammatory conditions. This led us to investigate the role of IL-17 in EAE. Strong antigen-specific production of IL-17 was demonstrated both in peripheral immune organs and in the CNS in acute and chronic EAE, as demonstrated by ELISPOT and RT-PCR analysis. Therapeutic neutralization of IL-17 with IL-17-receptor-Fc-protein in acute EAE ameliorated clinical symptoms. Neutralization of IL-17 with a monoclonal antibody also ameliorated the disease course. We conclude that IL-17 is crucially involved in the cytokine network as an effector cytokine in EAE.

Animals↗
PubMed2005

Assessment of lesion evolution in experimental autoimmune neuritis by gadofluorine M-enhanced MR neurography.

Experimental autoimmune neuritis (EAN) represents an animal model of acute inflammatory nerve injury mirroring pathophysiological aspects of the human Guillain-Barré syndrome. In the present study, we for the first time visualized the spatiotemporal evolution of autoimmune nerve injury and recovery by magnetic resonance imaging (MRI) by use of the novel micellar magnetic resonance (MR) contrast agent gadofluorine M (Gf). EAN was induced in Lewis rats by T-cell transfer (AT-EAN) leading to severe axonal damage, and Gf was applied intravenously at various disease stages mostly 24 h before MRI. In naive rats, Gf enhancement was present solely in the vascular compartment. In AT-EAN, clinically asymptomatic rats already showed consistent Gf uptake in spinal nerves on day 3, while sciatic nerves were spared. The cauda equina correspondingly exhibited massive T-cell infiltration. Gf enhancement further extended to the plexus lumbosacralis on day 4. On days 5 and 6, the entire peripheral neuraxis from the cauda equina, along the sciatic down to the tibial and peroneal nerves, showed strong Gf enhancement. Spinal and peripheral nerves now exhibited massive inflammation and axonal injury on parallel histological analysis. Gf enhancement persisted in the afflicted nerves until complete recovery and disappeared with a proximodistal gradient. In conclusion, Gf-enhanced MR neurography opens a new avenue for monitoring nerve damage in-vivo during an immune attack.

Animals↗
PubMed2005

Permanent effector phenotype of neuroantigen-specific T cells acquired in the central nervous system during experimental allergic encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is regarded as an animal model of the human autoimmune disease multiple sclerosis (MS). Autoreactive T cells are present in the peripheral T cell repertoire of healthy mice and mediate clinical autoimmune disease only after activation by immunization or pathogens and migrate into the central nervous system (CNS). Because it is not known whether autoreactive T cells are regulated differentially once entering the CNS we investigated cytokine regulation in T cells from peripheral lymphatic organs and from the inflamed CNS ex vivo obtained from SJL mice after inducing relapsing-remitting EAE with PLP peptide 139-151. We show here that during acute EAE, an interleukin-2 (IL-2) biased T cell response exists in the spleen, while an interferon-gamma (IFN-gamma) biased T cell response prevails in the CNS of mice with acute EAE. The IFN-gamma biased phenotype was stable with optimized costimulation and even after in vitro stimulation with IL-2. After adoptive transfer into naïve syngeneic mice these T cells were only partially reversed to an IL-2 biased phenotype. These findings of our work suggest that a permanent effector phenotype of neuroantigen-specific T cells is finally acquired in the CNS in EAE.

Animals↗
PubMed2005

Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis.

CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein-specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.

Animals↗
PubMed2005

Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis.

Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common -866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p = 0.0015). The UCP2 -866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.

Adolescent↗
PubMed2005

Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice.

The major pathological hallmarks of multiple sclerosis (MS) comprise inflammation, demyelination with associated gliosis and axonal damage, which most likely correlates with persisting disability. Axonal damage can occur by several mechanisms. This article focuses on myelin disintegration and direct immune attack on axons by CD8-positive T-cells as two possible scenarios for axonal injury. As protoypic models, we investigated experimental autoimmune encephalomyelitis (EAE) in ciliary neurotrophic factor gene knockout mice (CNTF-/- mice) with severe myelin pathology and EAE in beta-2 microglobulin gene knockout mice (beta2m-/- mice) lacking CD8-positive T-cells. The results from these studies indicate that the trigger attack for axonal injury even in a well-defined experimental design can be multi-faceted. No single factor seems to be absolutely necessary for the initiation of the process, but they rather act in concert and orchestrate tissue destruction, inflammation and regeneration. Some mechanisms of primary or secondary axonal damage may be shared between inflammatory and degenerative diseases of the nervous system, thereby establishing a link which might be of importance for future therapeutic strategies.

Amyloid beta-Protein Precursor↗
PubMed2005

Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG.

In generalized myasthenia gravis (MG) patients without detectable acetylcholine receptor (AChR) antibodies (SNMG), the thymus is often reported as "normally involuted." We analyzed thymic compartments in 67 patients with generalized MG, with AChR antibodies (AChR+, n = 23), with muscle-specific kinase (MuSK) antibodies (MuSK+, n = 14) or with neither (MuSK-, n = 30), and in 11 non-MG controls. Four of 14 MuSK+ thymi had rare small germinal centers, but overall they were not different from age-matched controls. However, approximately 75% MuSK- samples showed lymph node-type infiltrates similar to those in AChR+ patients, but with fewer germinal centers. These variations may explain some apparent differences in responses to thymectomy in SNMG.

Adolescent↗
PubMed2005

A CTLA4high genotype is associated with myasthenia gravis in thymoma patients.

Myasthenia gravis (MG) in thymoma patients depends critically on intratumorous generation and export of mature autoreactive CD4+ T cells. Why non-MG thymomas fail to produce CD4+ T cells is unknown. We studied three single-nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4(CTLA4) gene in thymoma patients, nonthymoma early-onset MG patients, and control subjects. Surprisingly, the CTLA4high genotype +49A/A, which is protective against several autoimmune diseases, exerted a prominent predisposing effect to paraneoplastic MG in thymoma patients. The unusual disease association with a CTLA4high genotype implies a unique pathogenesis of paraneoplastic MG, with high CTLA4 levels possibly supporting the nontolerogenic selection of CD4+ T cells in MG-associated thymomas.

Adolescent↗
PubMed2005

Genomics, proteomics, metabolomics: what is in a word for multiple sclerosis?

PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. RECENT FINDINGS: The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale single-nucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. SUMMARY: The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodegenerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Animals↗
PubMed2005

New Glucocorticoids on the Horizon: Repress, Don't Activate!

Glucocorticoids are highly effective drugs; their immunosuppressive and antiinflammatory actions are used in the treatment of many rheumatic and other inflammatory diseases. However, their use is sometimes considerably limited by numerous adverse reactions. For this reason, great efforts have been made in recent years to develop innovative glucocorticoids or glucocorticoid receptor ligands that have improved therapeutic effect/adverse reaction ratio. We summarize the position and critically discuss the following products that are currently under development: (1) selective glucocorticoid receptor agonists (SEGRA or dissociating glucocorticoids); (2) nitrosteroids; and (3) long-circulating liposomal glucocorticoids. Finally, we describe the state of research on membrane-bound glucocorticoid receptors as possible further targets for specific glucocorticoid actions.

Journal Article↗
PubMed2005

New glucocorticoids on the horizon: repress, don't activate!

Glucocorticoids are highly effective drugs; their immunosuppressive and antiinflammatory actions are used in the treatment of many rheumatic and other inflammatory diseases. However, their use is sometimes considerably limited by numerous adverse reactions. For this reason, great efforts have been made in recent years to develop innovative glucocorticoids or glucocorticoid receptor ligands that have improved therapeutic effect/adverse reaction ratio. We summarize the position and critically discuss the following products that are currently under development: (1) selective glucocorticoid receptor agonists (SEGRA or dissociating glucocorticoids); (2) nitrosteroids; and (3) long-circulating liposomal glucocorticoids. Finally, we describe the state of research on membrane-bound glucocorticoid receptors as possible further targets for specific glucocorticoid actions.

Animals↗
PubMed2004

Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis.

PURPOSE: Thymic epithelial tumors (TET) are rare epithelial neoplasms of the thymus with considerable histologic heterogeneity. This retrospective study focused on the correlation of WHO-defined TET histotypes with survival and tumor recurrence in a large cohort of patients receiving different modes of treatment. PATIENTS AND METHODS: Two hundred twenty-eight patients were followed for up to 21 years (median, 60 months; range, 1 to 252 months) after primary surgery. Forty-two patients received adjuvant radiotherapy (mean dose, 53 Gy), and 33 patients received adjuvant chemotherapy. RESULTS: Seventy-six (88%) of 86 patients with WHO type A, AB, and B1 thymomas were treated by surgery alone, with three tumor relapses after 3 to 10 years (median, 3.4 years). Twelve of 67 patients with WHO type B2 and B3 thymomas in Masaoka stages I and II were treated by adjuvant radiotherapy without evidence of tumor recurrence after 1 to 12 years (median, 4 years). Among 75 patients with B2 and B3 thymomas with incomplete resection or a tumor stage III or higher, the recurrence rate was 34% (n = 23) after 0.5 to 17 years (median, 5 years) in patients receiving adjuvant radiochemotherapy, compared to 78% (seven of nine patients) in patients without adjuvant radiochemotherapy. Incomplete tumor resection was associated with a high recurrence rate (65%) and a poor prognosis (P <.01). CONCLUSION: The long-term outcome of TET patients is related to tumor stage, WHO histotype, completeness of surgical removal, and type of treatment. Prospective trials are warranted to formally address the efficacy of adjuvant therapy in the treatment of localized and advanced malignant TETs.

Carcinoma, Squamous Cell↗
PubMed2004

Tolerance induction by intrathymic expression of P0.

Genetic deficiency or instability of myelin protein zero (P0) results in hereditary motor sensory neuropathy. In view of recent advances in gene therapy, substitution of the molecular defect may become realistic in the near future. Here we investigate the impact of genetic deficiency of P0 on selection of the autoreactive T cell repertoire in the corresponding mouse model. We show that P0 mRNA transcripts are expressed in thymic stroma, similar to other myelin proteins and that expression of intact P0 protein can be detected by Western blot. Using a library of overlapping 20mer peptides spanning the entire length of P0 and applying the ELISPOT technique, we detected a strong immune response toward P0 extracellular domain peptide aa 41-60 in P0(-/-) knockout mice, but not in heterozygous P0(+/-) or wild-type (wt) mice. In addition, one cryptic epitope and two subdominant epitopes of P0 were identified. Using P0(-/-) into wt bone marrow (BM) chimeras we found that P0 expression in the host suffices for full tolerance induction, which is in line with its presence in thymic stroma. However, repopulation of P0(-/-) mice with wt BM led to partial induction of tolerance, suggesting that BM derived cells can also express this protein. Our findings may have implications for secondary autoimmunity developing after gene therapy in hereditary neuropathies and other diseases with genetically determined protein deficiency, because the repaired protein will then represent a foreign, nontolerized Ag.

Amino Acid Sequence↗
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

In vivo monitoring of macrophage infiltration in experimental autoimmune neuritis by magnetic resonance imaging.

We report on the in vivo assessment of macrophage infiltration in adoptive transfer experimental autoimmune neuritis (AT-EAN), a prototypic Th-1-mediated autoimmune disorder of the peripheral nervous system (PNS). Lewis rats received systemic injections of superparamagnetic iron oxide (SPIO) particles at days 2, 3, 4, 5, or 9 after adoptive transfer of P2-specific T-cells and were scanned by standard 1.5 T magnetic resonance imaging (MRI) always 24 h later. MRI revealed focal signal loss of the cauda equina indicating iron accumulation in spinal nerves already at the preclinical stage (day 3). Signal loss peaked at day 4, when first clinical signs developed. At the maximum of clinical disease, signal loss already declined and disappeared on days 6 and 10. In spinal nerve sections, Perl's iron stain showed focal cellular accumulation of SPIO at days 3, 4, and 5 in ED1-positive macrophages. Spinal nerves at days 6 and 10 exhibited massive macrophage infiltrates, but no more iron deposition. In conclusion, SPIO-enhanced MRI provides a novel in vivo tool to assess the timing of macrophage entry into target tissues during an immunopathologic attack and holds promise to monitor immunotherapeutic interventions.

Animals↗