Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been demonstrated in our previous work that, in the human skin-grafting model, the expression of costimulatory molecule B7H1 (PD-L1) by keratinocytes plays an essential role in inducing local tolerance via activation of IL-10-secreting T cells. This study further analyzes the role of B7H1 in differentiation of type 1 T regulatory (Tr1) cells and explores underlying mechanisms. Mouse fusion protein B7H1-Ig is used, together with immobilized anti-CD3 mAb, to costimulate the purified naive CD4+ T cells. B7H1-Ig-treated CD4+ T cells were found to activate a characteristic Tr1 population possessing a CD4+ CD25- Foxp3- CD45RBlow phenotype. These regulatory T cells strongly inhibited the Th1-dominated MLR by secretion of IL-10 and TGF-beta. Moreover, B7H1-treated Tr1 cells also resulted in suppressed clinical scores and demyelination when adoptively transferred into mice with experimental allergic encephalomyelitis. Furthermore, analysis of the cytokine profile indicated that there were two differential reaction patterns during the B7H1-Ig-induced Tr1 development. These two patterns were characterized by activation of IFN-gammaR+ IL-10R- Th1 and IFN-gammaR+ IL-10R+ Tr1 cells, respectively. Secretion of IFN-gamma by Th1 and the expression of IFN-gammaR on Tr1 were critical for further Tr1 differentiation, as demonstrated by mAb blocking and by analysis in IFN-gamma(-/-) mice. In conclusion, B7H1 is capable of inducing Tr1 differentiation from naive CD4+ T cells by coactivation in an IFN-gamma- or Th1-dependent manner. Our study may shed some light upon the clinical usage of B7H1 as a therapeutic reagent for induction of tolerance.
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PMID:B7H1-Ig fusion protein activates the CD4+ IFN-gamma receptor+ type 1 T regulatory subset through IFN-gamma-secreting Th1 cells. 1695 20

Experimental autoimmune encephalomyelitis is a well-characterized model of cell-mediated autoimmunity. TLRs expressed on APCs recognize microbial components and induce innate immune responses, leading to the elimination of invading infectious agents. Certain TLR agonists have been reported to have adjuvant properties in CNS autoimmune inflammatory demyelination. We report in this study that TLR3 stimulation by polyinosinic-polycytidylic acid, a double-stranded RNA analog, suppresses relapsing demyelination in a murine experimental autoimmune encephalomyelitis model. Disease suppression is associated with the induction of endogenous IFN-beta and the peripheral induction of the CC chemokine CCL2. These data indicate that a preferential activation of the MyD88-independent, type I IFN-inducing TLR pathway has immunoregulatory potential in this organ-specific autoimmune disease.
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PMID:Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. 1711 17

The 1,25(OH)(2)D(3) analog, TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)), has an interesting dissociation profile between its potent immunomodulatory and its calcemic effects in vivo. The strong immunomodulatory potency of TX527 is reflected by its ability to attenuate experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). At present most MS patients are being treated with systemic IFN-beta administration. The aim of this study was to investigate whether combining IFN-beta with TX527 could empower its EAE-protective effects. We evaluated also combinations with the standard immunosuppressant cyclosporin A (CsA). EAE was induced in SJL mice by PLP immunization, treatment was started 3 days before disease induction. The TX527+IFN-beta combination resulted in significant disease protection which was superior to the effect of both treatment separately. No disease amelioration, even aggravation, was obtained with the IFN-beta+CsA combination. By adding TX527 to the IFN-beta+CsA combination near complete protection from EAE was achieved (100% protection from paralysis, mean maximal score of 1.8+/-1.5, both p<0.05 versus controls and all individual treatments). From these data we conclude that adding TX527 to an IFN-beta and/or CsA treatment results in clear additional immunomodulatory effects in EAE prevention and is therefore a potentially interesting candidate to be considered in clinical intervention trials in MS.
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PMID:Novel insights in the immune function of the vitamin D system: synergism with interferon-beta. 1725 71

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.
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PMID:The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma. 1732 Sep 75

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the CNS that is used to model certain parameters of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE, we assessed the incidence of EAE and these parameters in mice lacking NF-kappaB, TNF-alpha, IFN-alphabeta receptors, IFN-gamma receptors, and inducible nitric oxide synthase. Although increased myelin oligodendrocyte glycoprotein-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity, the loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real-time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. On the other hand, disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity seems to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators.
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PMID:Loss of blood-brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models. 1737 91

Sindbis virus (SINV) is an alphavirus that causes infection of neurons and encephalomyelitis in adult immunocompetent mice. Recovery can occur without apparent neurological damage. To better define the factors facilitating noncytolytic clearance of SINV in different regions of the central nervous system (CNS) and the roles of innate and adaptive immune responses at different times during infection, we have characterized SINV infection and clearance in the brain, brain stem, and spinal cords of severe combined immunodeficiency (SCID) and C57BL/6 (wild-type [WT]) mice and mice deficient in beta interferon (IFN-beta) (BKO), antibody (muMT), IFN-gamma (GKO), IFN-gamma receptor (GRKO), and both antibody and IFN-gamma (muMT/GKO). WT mice cleared infectious virus by day 8, while SCID mice had persistent virus replication at all sites. For 3 days after infection, BKO mice had higher titers at all sites than WT mice, despite similar IFN-alpha production, but cleared virus similarly. GKO and GRKO mice cleared infectious virus from all sites by days 8 to 10 and, like WT mice, displayed transient reactivation at 12 to 22 days. muMT mice did not clear virus from the brain, and clearance from the brain stem and lumbar spinal cord was delayed, followed by reactivation. Eighty-one days after infection, muMT/GKO mice had not cleared virus from any site, but titers were lower than for SCID mice. These studies show that IFN-beta is independently important for early control of CNS virus replication, that antiviral antibody is critical for clearance from the brain, and that both antibody and IFN-gamma contribute to prevention of reactivation after initial clearance.
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PMID:Synergistic roles of antibody and interferon in noncytolytic clearance of Sindbis virus from different regions of the central nervous system. 1737 10

Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-gamma, a cytokine not normally expressed in the CNS. To investigate the role of IFN-gamma in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-gamma (AdIFNgamma) to IFN-gamma-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-gamma that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-gamma induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-gammaR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-gamma-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-gamma vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-gamma induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-gamma-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.
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PMID:IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system. 1754 56

The importance of the IL-12/IFN-gamma/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-gamma/NO axis in the development of MOG 35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-gamma receptor (IFN-gammaR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-gamma production in IL-12-/- mice and the lack of IFN-gamma/IFN-gammaR signaling pathway in IFN-gammaR-/- mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12-/-, IFN-gammaR-/- and NOS2-/- compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12-/-, IFN-gammaR-/- and NOS2-/-mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN-gamma/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production.
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PMID:IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis. 1769 13

Ethyl 2-[4-(12-beta-artemisininoxy)]phenoxylpropionate (SM933) is a novel derivative of artemisinin, an herbal compound approved for the treatment of malaria. In this study, we show that SM933 has unique anti-inflammatory properties through regulation of signaling pathways, leading to amelioration of experimental autoimmune encephalomyelitis. The anti-inflammatory properties of SM933 were characterized by inhibition of encephalitogenic T cell responses that were altered to exhibit a Th2 immune deviation and reduced activity and concentration of NO and inducible NO synthase. The observed effect of SM933 was mediated through regulatory mechanisms involving the NFkappaB and the Rig-G/JAB1 signaling pathways. SM933 was found to inhibit the activity of NFkappaB by up-regulating IkappaB, which accounted for various down-stream anti-inflammatory actions. Furthermore, it up-regulated Rig-G through the action of IFN-alpha and prevented JAB1, a master cell cycle regulator, from entering the nucleus to promote p27 degradation, resulting in down-regulation of CDK2 and cyclin A and cell cycle progression. Regulation of the Rig-G/JAB1 pathway by SM933 led to altered cell cycle activity of encephalitogenic T cells as a result of its selective effect on activated, but not resting, T cells. The study indicates that SM933 is a novel anti-inflammatory agent acting through defined signaling mechanisms and provides regulatory mechanisms required for effective drug targeting in treatment of autoimmune disease and inflammation.
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PMID:Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis. 1794 69

Excessive inflammation occurs during infection and autoimmunity in mice lacking the alpha-subunit of the interleukin 27 (IL-27) receptor. The molecular mechanisms underlying this increased inflammation are incompletely understood. Here we report that IL-27 upregulated IL-10 in effector T cells that produced interferon-gamma and expressed the transcription factor T-bet but did not express the transcription factor Foxp3. These IFN-gamma+T-bet+Foxp3- cells resembled effector T cells that have been identified as the main source of host-protective IL-10 during inflammation. IL-27-induced production of IL-10 was associated with less secretion of IL-17, and exogenous IL-27 reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis by a mechanism dependent on IL-10. Our data show that IL-27-induced production of IL-10 by effector T cells contributes to the immunomodulatory function of IL-27.
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PMID:Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. 1802 76


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