Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) is a devastating autoimmune disease that affects more than 1 million people worldwide and severely compromises motor and sensory function through demyelination and axonal loss. This review covers current therapies, lessons learned from failed clinical trials, genetic susceptibility, key cell types involved, animal models, gene expression, and biomarker information. The current first-line therapies for MS include the type I interferons (IFN-I) and glatiramer acetate (GA) but because of their limited effectiveness new therapeutic modalities are required. Tysabri is an anti very late antigen-4 antibody that antagonizes the migration of multiple cell types and appears more efficacious as compared to the IFNs or GA. Tysabri blocks the transmigration of T cells and monocytes, which indicates that blocking multiple cell types may increase the effectiveness of the therapy. However, this therapy may increase the risk of progressive multifocal leukoencephalopathy. The major cell types hypothesized to be pathogenic include T cells and antigen-presenting cells, including B cells. The correlation of the animal model experimental autoimmune encephalomyelitis (EAE) of MS and its predictive value to determine efficacy in the clinic appears limited. However, all current therapies do demonstrate efficacy in EAE models. There are also examples of mechanisms that have worked in EAE but have failed in the clinic, such as the TNFα antagonists and anti-p40 (a subunit of IL-12 and IL-23). The MS field would benefit if clinical biomarkers were available to monitor clinical efficacy. The etiology of MS remains elusive but additional understanding of mechanisms involved in the pathogenesis of MS may guide us to more effective treatment and management of this autoimmune disease.
 ...
PMID:Pathogenic mechanisms and experimental models of multiple sclerosis. 2038 May 90

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. Researchers have only limited access to early and immunologically active MS tissue samples, and the modification of experimental circumstances is much more restricted in human studies compared to studies in animal models. For these reasons, animal models are needed to clarify the underlying immune-pathological mechanisms and test novel therapeutic and reparative approaches. It is not possible for a single mouse model to capture and adequately incorporate all clinical, radiological, pathological and genetic features of MS. The three most commonly studied major categories of animal models of MS include: (1) the purely autoimmune experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally induced chronic demyelinating disease models, with the main model of Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, including the cuprizone model and focal demyelination induced by lyso-phosphatidyl choline (lyso-lecithine). EAE has been enormously helpful over the past several decades in our overall understanding of CNS inflammation, immune surveillance and immune-mediated tissue injury. Furthermore, EAE has directly led to the development of three approved medications for treatment in multiple sclerosis, glatiramer acetate, mitoxantrone and natalizumab. On the other hand, numerous therapeutical approaches that showed promising results in EAE turned out to be either ineffective or in some cases harmful in MS. The TMEV model features a chronic-progressive disease course that lasts for the entire lifespan in susceptible mice. Several features of MS, including the role and significance of axonal injury and repair, the partial independence of disability from demyelination, epitope spread from viral to myelin epitopes, the significance of remyelination has all been demonstrated in this model. TMEV based MS models also feature several MRI findings of the human disease. Toxin-induced demyelination models has been mainly used to study focal demyelination and remyelination. None of the three main animal models described in this review can be considered superior; rather, they are best viewed as complementary to one another. Despite their limitations, the rational utilization and application of these models to address specific research questions will remain one of the most useful tools in studies of human demyelinating diseases.
 ...
PMID:The relevance of animal models in multiple sclerosis research. 2053 77

The aim of this study was to identify cell populations relevant to pathogenesis and repair within the injured CNS in mice that recovered from experimental autoimmune encephalomyelitis (EAE). We demonstrate that in two EAE models, with either relapsing-remitting or chronic course, T-cells and resident activated microglia manifested extensive IL-17 expression, with apparent localization within regions of myelin loss. In mice treated with glatiramer acetate (GA, Copaxone), even when treatment started after disease exacerbation, CNS inflammation and Th-17 occurrence were drastically reduced, with parallel elevation in T-regulatory cells, indicating the immunomodulatory therapeutic consequences of GA treatment in situ.
 ...
PMID:Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing-remitting or chronic EAE. 2055 28

Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration-approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.
 ...
PMID:Translational research in neurology and neuroscience 2010: multiple sclerosis. 2062 66

We recently showed that B cells reduce CNS inflammation in mice with experimental allergic encephalomyelitis (EAE). Here, we demonstrate that adoptively transferred CD5/CD19+ B cells protect against EAE severity. Furthermore, we show that glatiramer acetate (GA), a therapeutic for relapsing multiple sclerosis treatment, amplifies this effect. Transfer of GA-conditioned B cells leads to increased production of immunoregulatory cytokines and reduced CNS inflammation, as well as decreased expression of the chemokine receptor, CXCR5, and elevated BDNF expression in the CNS. Thus B cells can protect against EAE, and GA augments this effect in maintaining immune homeostasis and controlling EAE disease progression.
 ...
PMID:Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. 2111 89

Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clinical effect to a shift in the cytokine secretion of CD4+ T helper (T(h)) cells, growing evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is associated with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ T(h) cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody production by plasma cells have been reported; in addition, most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Experimental evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer's or Parkinson's disease. In this review, we provide a comprehensive and critical overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.
 ...
PMID:Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. 2147 11

Glatiramer acetate, a mixture of synthetic polypeptides able to prevent autoimmune encephalomyelitis in experimental models, is used as a treatment for patients with active relapsing-remitting multiple sclerosis. We report one case of glatiramer acetate induced hepatitis. Liver biopsy was consistent with a diagnosis of drug induced hepatitis and alanine aminotransferase returned to normal values after treatment discontinuation. The present case should serve as a warning that glatiramer acetate may cause acute liver disease.
 ...
PMID:Acute hepatitis induced by glatiramer acetate. 2168 65

The respective roles of inflammatory and neurodegenerative processes in the pathology of multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. Novel treatment strategies aim to operate within the CNS to induce neuroprotection and repair processes in addition to their anti-inflammatory properties. In this study we analyzed and compared the in situ pathological manifestations of EAE utilizing two different models, namely the relapsing-remitting PLP-induced and the chronic MOG-induced diseases. To characterize pathological changes, both transmission electron microscopy (TEM) and immunohistochemistry were employed. The effect of the approved MS drug glatiramer acetate (GA, Copaxone) on myelin damage/repair and on motor neuron loss/preservation was studied in both EAE models. Ultrastructural spinal cord analysis revealed multiple white matter damage foci, with different patterns in the two EAE models. Thus, the relapsing-remitting model was characterized mainly by widespread myelin damage and by remyelinating fibers, whereas in the chronic model axonal degeneration was more prevalent. Loss of lower motor neurons was manifested only in mice with chronic MOG-induced disease. In the GA-treated mice, smaller lesions, increased axonal density and higher prevalence of normal appearing axons were observed, as well as decreased demyelination and degeneration. Furthermore, quantitative analysis of the relative remyelination versus demyelination, provides for the first time evidence of significant augmentation of remyelination after GA treatment. The loss of motor neurons in GA-treated mice was also reduced in comparison to that of EAE untreated mice. These effects were obtained even when GA treatment was applied in a therapeutic schedule, namely after the appearance of clinical symptoms. Hence, the remyelination and neuronal preservation induced by GA are in support of the neuroprotective consequences of this treatment.
 ...
PMID:Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate. 2175 99

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t(1/2) ~1 h), or a slow, zero-order release rate (t(1/2) ~ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies.
 ...
PMID:Fabrication principles and their contribution to the superior in vivo therapeutic efficacy of nano-liposomes remote loaded with glucocorticoids. 2199 84

Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination.
 ...
PMID:Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. 2200 4


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>