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)

Axonal destruction and neuronal loss occur early during multiple sclerosis (MS), an autoimmune inflammatory central nervous system disease that frequently manifests with acute optic neuritis. Glatiramer acetate (GA) and interferon-beta-1b (IFN-beta-1b) are two immunomodulatory agents that have been shown to decrease the frequency of MS relapses. However, the question of whether these substances can slow neurodegeneration in MS patients is the subject of controversy. In a rat model of experimental autoimmune encephalomyelitis, we investigated the effects of GA and IFN-beta-1b on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. For each substance, therapy was started 14 days before immunization, on the day of immunization, or on the day of clinical disease onset. After myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of RGCs was measured by electroretinograms. Although early GA or IFN-beta-1b treatment showed benefit on disease activity, only treatment with GA exerted protective effects on RGCs, as revealed by measuring neurodegeneration and neuronal function. Furthermore, we demonstrate that this GA-induced neuroprotection does not exclusively depend on the reduction of inflammatory infiltrates within the optic nerve.
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PMID:Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study. 1700 91

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.
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PMID:Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. 1738 65

The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and rate-limiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-beta and interferon-gamma and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-gamma-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.
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PMID:IDO expression in the brain: a double-edged sword. 1759 69

Interferon-beta (IFN-beta), an approved treatment of multiple sclerosis (MS), produces only partial clinical responses. IFN-beta therapy has been limited by its short serum half-life and limited ability to cross the blood brain barrier. We have developed a means of delivering the IFN-beta gene both systemically and into the central nervous system (CNS) using bone marrow stem cells (BMSCs) as a vehicle and examined the therapeutic efficacy of this approach in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. A retroviral expression vector (pLXSN-IFNbeta) was used to stably transfect virus producer PA317 cells to generate retrovirus containing the IFN-beta gene which then was used to transduce BMSCs. IFN-beta engineered BMSCs were transplanted (i.v.) into mice that then were immunized with proteolipoprotein (PLP) to initiate EAE. IFN-beta-engineered BMSCs transplanted mice showed a significant inhibition of EAE onset, and the overall clinical severity was less compared to control groups. IFN-beta delivery strongly reduced infiltration of mononuclear cells possibly by inhibiting cell adhesion molecules. Reduced demyelination and increased remyelination were also observed in the IFN-beta treated group. Furthermore, inhibition of the pro-inflammatory cytokines TNF-alpha, IFN-gamma and IL-12 and enhanced expression of the anti-inflammatory cytokines IL-10, IL-4 and TGF-beta was observed in CNS tissue. In addition, mice receiving IFN-beta had reduced apoptosis and increases in growth promoting factors including BDNF, CNTF, PDGF and VEGF. These results suggest that BMSCs can be used as vehicles to deliver the IFN-beta into the CNS. This is a potentially novel therapeutic approach which might be used in MS and other diseases of the CNS in which drug access is limited.
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PMID:Stem cell based delivery of IFN-beta reduces relapses in experimental autoimmune encephalomyelitis. 1847 98

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Fortunately, progress has been made for patients with this devastating disorder thanks to the induction of novel treatment strategies. In the 1990s, autoimmunity against myelin-related proteins was verified in humans, while the molecular mechanisms of the pathological process resulting in CNS demyelination were also studied in depth using experimental autoimmune encephalomyelitis (EAE). In the present decade, those achievements led to clinical trials of a variety of monoclonal antibody reagents for preventing disease relapse. Although such treatment seems to be ideal, as it targets a specific harmful immune reaction on the basis of findings from EAE studies, it has yet to become a first-line strategy, because of, in part, unexpected serious adverse reactions. As a result, interferon-beta therapy, the efficacy of which was first reported in 1993. has maintained a good position among treatment options for suppressing disease activity. Interferon-beta is considered to exert its anti-inflammatory effect via a Th2 shift in immune responses. In addition to aberrant cellular immunity, recent progress in MS research has shed light on the involvement of disturbances in humoral immunity, including the presence of NMO-IgG and anti-aquaporin-4 antibodies. Thus, it is important to elucidate the pathological significance of those autoantibodies, as well as establish treatment strategies for patients who are positive for them. However, since the above-mentioned treatments have been developed only for patients with relapsing-remitting MS. it is also important to consider the pathogenesis of primary progressive MS, which constitutes 10-15% of the patient population. Neurologists cannot be indifferent to current studies on MS, as even viral etiologies long ago abandoned have been recently revisited. In this field of neurology, every step of progress may readily lead to the establishment of a new treatment options.
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PMID:[Progress in unravelling the etiology of multiple sclerosis]. 1919 98

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Despite a variety of anti-inflammatory or immunomodulation drugs including interferon-beta are effective to reduce relapse risk, most patients have progressive neurological deterioration due to axonal degeneration. Accumulation of activated microglia is a pathological hallmark of active MS lesion. Microglia can act as not only antigen-presenting cells but also effector cells to damage other cells in the central nervous system. Especially, glutamate released by activated microglia induces excito-neurotoxicity and may contribute to neurodegeneration in MS. Gap junction is a major cell-to-cell channel and is composed of paired hemichannels on coupled cells. Recent studies showed that cells release various small molecules (including ions, ATP, and amino acids) from unpaired hemichannel of gap junction that is openly exposed to the extracellular space. We have previously revealed that activated microglia produce glutamate via glutaminase and release it through hemichannels of gap junctions. Thus, in this study, we examined whether the glutaminase inhibitor and the gap junction blocker relieved experimental autoimmune encephalomyelitis (EAE) that is an animal model of MS. Here we show that the gap junction blocker carbenoxolone (CBX) and the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) decreased glutamate release from activated microglia and rescued neuronal death in a dose-dependent manner in vitro. In EAE mice, treatment with CBX or DON also attenuated EAE clinical symptoms. Thus, blockade of glutamate release from activated microglia with CBX or DON may be an effective therapeutic strategy against neurodegeneration in MS.
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PMID:Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. 1921

Multiple sclerosis (MS) remains without an effective treatment in spite of intense research efforts. Interferon-beta (IFN-beta) reduces duration and severity of symptoms in many relapsing-remitting MS patients, but its mechanism of action is still not well understood. Moreover, IFN-beta and other available treatments must be given parenterally and have a variety of adverse effects. Certain naturally occurring flavonoids, such as luteolin, have anti-oxidant and anti-inflammatory effects, including inhibition of activated peripheral blood leukocytes from MS patients. Luteolin also inhibits mast cells, as well as mast cell-dependent T cell activation, recently implicated in MS pathogenesis. Moreover, luteolin and structurally similar flavonoids can inhibit experimental allergic allergic encephalomyelitis (EAE), an animal model of MS in rodents. An appropriate luteolin formulation that permits sufficient absorption and reduces its metabolism could be a useful adjuvant to IFN-beta for MS therapy.
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PMID:Luteolin as a therapeutic option for multiple sclerosis. 1982 65

Non-CNS chemokine production may contribute to previously unrecognised components of Multiple Sclerosis (MS) pathology. Here we show that IL-8, a neutrophil chemoattractant, is significantly increased in serum from individuals with MS, and that the rodent homolog of IL-8 (CXCL1) is expressed in the liver in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. The hepatic expression of CXCL1 in EAE is accompanied by neutrophil recruitment to the liver, and we show that this recruitment is a feature of post mortem liver tissue from MS patients, which is a previously unrecognised phenomenon. We speculated that the presence of peripheral CXC-chemokine expression might contribute to the sickness behaviours associated with MS, which are a significant contributor to morbidity. Peripheral, but not central, administration of CXCL1 to Wistar rats inhibited spontaneous activity in the open field and burrowing behaviour in a dose-dependent manner (5-45 microg). The expression of CXCL1 by the liver and the recruitment of neutrophils can be modelled by the intracerebral injection of IL-1beta. Here, we found that interferon-beta (IFN-beta) pretreatment significantly inhibited hepatic CXCL1 production and neutrophil recruitment to the liver induced by the microinjection of IL-1beta into the brain. Thus while the mechanism by which IFN-beta therapy suppresses disease in MS remains unclear, the data presented here suggests that the inhibition of hepatic chemokine synthesis may be a contributing factor.
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PMID:Sickness behaviour is induced by a peripheral CXC-chemokine also expressed in multiple sclerosis and EAE. 2013 39

Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-beta was effective in reducing EAE symptoms induced by T helper type 1 (T(H)1) cells but exacerbated disease induced by T(H)17 cells. Effective treatment in T(H)1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In T(H)17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-beta treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-gamma. In the absence of IFN-gamma signaling, IFN-beta therapy was ineffective in EAE. In RRMS patients, IFN-beta nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-beta is proinflammatory in T(H)17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-beta.
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PMID:T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. 2037 43

Multiple sclerosis (MS) is assumed to be an autoimmune disease initiated by autoreactive T cells that recognize central nervous system antigens. Although adaptive immunity is clearly involved in MS pathogenesis, innate immunity increasingly appears to be implicated in the disease. We and others have presented evidence that natural killer (NK) cells may be involved in immunoregulation in MS, leading to the question of whether a particular NK cell subtype will account for this effect. Changes of NK cell functionality in MS were associated with MS activity, and depletion of NK cells exacerbated the course of disease in a murine model of MS, experimental autoimmune encephalomyelitis. Several studies described a deficiency and transient "valleys" in NK cell killing activity in human MS, which may coincide with symptomatic relapse. However, the molecular basis of the defect in killing activity has not been determined. We discuss results on the expression of perforin in CD16(+) NK cells and the existence of an inverse relationship between myelin loaded phagocytes and the proportion of CD16(+) NK cells expressing perforin in the circulation. This inverse relationship is consistent with a role for NK cell killing activity in dampening autoimmunity. On the other hand, it has been broadly reported that first line MS therapies, such as interferon-beta, glatiramer acetate as well as escalation therapies such as fingolimod, daclizumab, or mitoxantrone seem to affect NK cell functionality and phenotype in vivo. Therefore, in this review we consider evidence for the immunoregulatory role of NK cells in MS and its animal models. Furthermore, we discuss the effect of MS treatments on NK cell activity.
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PMID:The role of natural killer cells in multiple sclerosis and their therapeutic implications. 2349 80


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