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)

Some activities of retinoids on cellular and humoral immunity have been described, but the available data are conflicting or obtained at concentrations that are toxic in vivo. In this study, we demonstrate that 13-cis-retinoic acid (13-cRA), a retinoid well tolerated in human therapy, can suppress T cell-mediated immunity in rats. Treatment with pharmacological concentrations of 13-cRA prevented active as well as passive transfer experimental autoimmune encephalomyelitis (EAE) and suppressed lymphocyte responsiveness to T cell mitogens, suggesting that the drug activity included suppression of an effector T cell response. In addition, mitogen- and antigen-induced lymphocyte proliferation was inhibited in vitro in the presence of concentrations of 13-cRA equivalent to or less than those achieved in vivo, further suggesting that the prevention of EAE was due to a suppressive activity on T cell-mediated immunity. The immunosuppressive activity of 13-cRA included suppression of interleukin 2, whose production was inhibited in splenocytes. These data indicate that, in an in vivo mammalian system, 13-cRA exerts a suppressive activity on T cell-mediated immunity intensive enough to suppress an ongoing immune response, and that this effect can be achieved at nontoxic concentrations that may also be attained in human therapy.
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PMID:Immunosuppressive activity of 13-cis-retinoic acid and prevention of experimental autoimmune encephalomyelitis in rats. 191 83

Administration of retinoic acid (RA) prevented the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. RA suspended in corn oil was given for 3 days before the expected onset of the disease to rats immunized with myelin and to controls. The drug suppressed the neurological symptoms as well as the perivascular infiltrates observed in vehicle-treated animals. The results indicate that under these experimental conditions, RA has immunosuppressive activity by interfering with the efferent phase of the immune response.
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PMID:Suppression of experimental allergic encephalomyelitis by retinoic acid. 349 30

Two form of retinoic acid (RA) prevented the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. RA suspended in corn oil was given before the expected onset of the disease to rats immunized with myelin and to controls. The drug suppressed the neurological symptoms as well as the perivascular infiltrates observed in vehicle treated animals. The results indicate that, under these experimental conditions, RA has immunosuppressive activity by interfering with the efferent phase of the immune response.
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PMID:The control of experimental allergic encephalomyelitis with retinoic acid. Further studies. 349 54

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelination. Retinoids regulate cell differentiation and growth by binding to and activating retinoic acid receptors, which seem to be nuclear transcription factors. The effect of retinoids on chronic relapsing EAE produced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the proliferation of MBP-specific LNC in vitro. However, the capacity of these cells to transfer EAE was markedly reduced by concentrations of tRA that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MBP-specific LNC activation resulted in a considerable increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-gamma was decreased. Increased IL-4 also was detected in culture supernatants. However, the presence of a neutralizing Ab to IL-4 (11B11) during MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given after disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 phenotype, which, in turn, might be responsible for the decrease in the encephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which the protective cytokines of Th2-like cells predominate may have potential relevance for human demyelinating diseases such as multiple sclerosis.
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PMID:Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. 752 21

Pharmacokinetics and pharmacodynamics of 13-cis-retinoic acid (13-cRA) administered at doses that suppress experimental autoimmune encephalomyelitis (EAE) have been investigated in rats. Serum concentration of the drug measured following oral administration of 37 mg/kg/12 h reached a peak of 1.8 x 10(-5) M in 2 h and linearly declined to 7.8 x 10(-7) M at hour 12. When spleen cells (SC) collected from 13-cRA-administered animals were cultured in vitro, their proliferative response to the T-cell mitogen concanavalin A (ConA) was suppressed and this effect was dependent on in vivo serum concentrations of the drug. In addition, in vitro exposure of antigen-specific T-cell lines to 13-cRA concentrations equivalent to those observed in vivo caused a dose-dependent suppression of the proliferation induced by the antigen as well as by T-cell mitogens. On a molar basis, 13-cRA showed a stronger in vitro immunosuppressive activity than two immunosuppressive agents used in human therapy, cyclosporin A and 6-mercaptopurin.
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PMID:Immunosuppressive activity of 13-cis-retinoic acid in rats: aspects of pharmacokinetics and pharmacodynamics. 940 38

Gene expression monitoring using gene expression microarrays represents an extremely powerful technology for gene discovery in a variety of systems. We describe the results of seven experiments using Incyte GEM technology to compile a proprietary portfolio of data concerning differential gene expression in six different models of neuronal differentiation and regeneration, and recovery from injury or disease. Our first two experiments cataloged genes significantly up- or down-regulated during two phases of the retinoic acid-induced differentiation of the embryonal carcinoma line Ntera-2. To identify genes involved in neuronal regeneration we performed three GEM experiments, which included changes in gene expression in rat dorsal root ganglia during the healing of experimentally injured sciatic nerve, in regenerating neonatal opossum spinal cord, and during lipopolysaccharide stimulation of primary cultures of rat Schwann cells. Finally we have monitored genes involved in the recovery phase of the inflammatory disease of the rat spinal cord, experimental allergic encephalomyelitis, as well as those responsible for protection from oxidative stress in a glutamate-resistant rat hippocampal cell line. Analysis of the results of the approximately 70,000 data points collected is presented.
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PMID:Gene expression monitoring for gene discovery in models of peripheral and central nervous system differentiation, regeneration, and trauma. 1107 84

To determine if retinoids might be beneficial in the treatment of multiple sclerosis (MS), all-trans-retinoic acid (tRA) was tested for its effects on proliferation and cytokine expression in human autoreactive T cells. tRA decreased human lymphocyte proliferation in vitro in a dose-dependent manner. In addition, tRA induced IL-4 gene expression in myelin basic protein (MBP)-specific T cell lines which had previously expressed a Th1-like phenotype. MBP-specific T cell lines generated in the presence of tRA had a Th2-like phenotype. Retinoids have previously been shown to have a similar effect on encephalitogenic T cells in experimental allergic encephalomyelitis (EAE; an animal model for MS) and treatment of EAE with retinoids stabilizes the disease. Since several oral retinoids have been shown to be safe in humans, retinoids may be beneficial in the treatment of MS.
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PMID:Retinoic acid promotes the development of Th2-like human myelin basic protein-reactive T cells. 1214 36

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors (RXRs) as PPAR-RXR heterodimers. In experimental autoimmune encephalomyelitis (EAE), the gene expression of PPAR-gamma was demonstrated in spinal cord during the course of EAE. Administration of 15-deoxy-(12,14)-prostaglandin J2 (15d-PGJ2) or 9-cis-retinoic acid (RA) alone at the onset of clinical signs of EAE reduced the severity of disease, however, their combination resulted in enhanced amelioration of disease. These results suggest that use of RXR specific ligands may be highly effective when combined with PPAR-gamma agonists in the treatment of autoimmune demyelinating diseases such as multiple sclerosis (MS).
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PMID:Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis. 1497 92

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.
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PMID:Hormone regulation of microglial cell activation: relevance to multiple sclerosis. 1585 Jun 70

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.
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PMID:Agonists for the peroxisome proliferator-activated receptor-alpha and the retinoid X receptor inhibit inflammatory responses of microglia. 1596 40


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