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)

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.
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PMID:Transgenic mouse model for central nervous system demyelination. 171 29

Experimental allergic encephalomyelitis (EAE) is a T cell mediated model of demyelinating disease that develops as a result of an autoimmune response to the myelin structural antigen, myelin basic protein (MBP). Much information has accumulated on the nature of trimolecular interactions which lead to the activation of self-reactive T lymphocytes in this disorder. Many parallels exist in the etiopathogenesis of EAE and multiple sclerosis (MS). Based upon these similarities selective immunotherapy that targets either class II molecules of the major histocompatibility complex or T cell receptor variable region genes will be described for EAE with consideration given to application of these principles in MS.
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PMID:Trimolecular interactions in experimental autoimmune demyelinating disease and prospects for immunotherapy. 171 84

Competition between peptides for binding to class II major histocompatibility complex (MHC) molecules has been demonstrated both in vitro and in vivo. Peptide competition may provide a way to interfere with T cell activation in the treatment of autoimmune diseases. It may be possible to provide a substitute 'blocking' peptide to compete for presentation of an autoantigenic peptide to T cells. The approach described is a general one, which may be applicable to a number of T cell mediated MHC-linked autoimmune diseases, and to other undesirable immune responses. So far, peptide competitors have only been successfully used in the prevention of experimental autoimmune encephalomyelitis (EAE). Whether or not this approach will work in treating spontaneous disease models remains to be tested, although work in other test systems is encouraging.
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PMID:Competitive inhibition of antigen presentation in animal models of autoimmune disease. 171 85

Experimental autoimmune encephalomyelitis (EAE) is an experimental demyelinating disease of rodents. In (PL/J x SJL) F1 mice, it is induced by immunization with the myelin basic protein peptide Ac1-11. Ac1-11 [4A], a myelin basic protein peptide analog with a single amino acid substitution, (i) binds to class II major histocompatibility complex molecules and stimulates encephalitogenic T cells in vitro better than Ac1-11, (ii) is nonimmunogenic and nonencephalitogenic in vivo in (PL/J x SJL)F1 mice, (iii) prevents EAE when administered before or at the time of immunization with Ac1-11, and (iv) prevents EAE when administered later, near the time of disease onset. Initial studies suggest that Ac1-11 [4A] does not prevent EAE by competitive inhibition or by activation of regulatory cells. Thus, substitution of a single amino acid in a myelin basic protein peptide confers the capacity to prevent rather than induce EAE, even after peptide-specific encephalitogenic T cells have been activated.
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PMID:A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. 171 36

SJL/J mice are highly susceptible to actively induced experimental allergic encephalomyelitis (EAE), whereas B10.S mice are not. Yet both strains share the H-2s major histocompatibility complex (MHC) haplotype. In order to help determine the cellular basis for the disparate susceptibility to EAE, the antigen-specific in vitro proliferative responses of lymph node (LN) T cells from SJL/J and B10.S mice primed with porcine myelin basic protein (MBP) were assessed. The results indicated that SJL/J mice were high responders and B10.S mice were low responders to both porcine and murine MBP, as demonstrated by limiting dilution analyses and cloning efficiency analysis of MBP-reactive T cells. The low response of B10.S mice to MBP was not due to elevated suppressor cell activity or to a discernible defect in antigen-presenting cell activity. Rather, it appeared to be due to a paucity (or defect in function) of high affinity MBP-reactive T cells in B10.S as compared to SJL/J mice. This difference in MBP responsiveness must, by necessity, be linked to non-MHC background genes. Therefore, assuming that the relative number of MBP-reactive T cells parallels that of EAE-effector T cells in SJL/J and B10.S mice (as separate in vivo studies indicate), the present results suggest that differences in the T cell repertoire for the encephalitogenic determinants of MBP may contribute significantly to the observed differences in antigen reactivity, and may relate to differences in susceptibility to EAE.
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PMID:Relative susceptibility of SJL/J and B10.S mice to experimental allergic encephalomyelitis is correlated with high and low responsiveness to myelin basic protein. 172 Jan 37

Experimental allergic encephalomyelitis is a T-cell-mediated, major histocompatibility complex (MHC) class II gene-linked autoimmune demyelinating disease of the central nervous system. To develop therapies that will specifically inactivate only the autoantigen-reactive T cells, mice were treated with soluble MHC class II molecules that had been complexed with encephalitogenic peptides. Intravenous injections of 300 micrograms of complexes consisting of encephalitogenic peptide 91-103 of myelin basic protein plus I-As protein on day 0, 4, and 7 were effective in preventing experimental allergic encephalomyelitis. Similarly, administration of 45 micrograms of I-As protein complexed to peptide 139-151 from proteolipoprotein on day 1, 4, and 7 prevented mortality and significantly reduced paralysis induced by immunization with the encephalitogenic proteolipoprotein peptide. Histological examination of sections of animal brains revealed that treatment with I-As protein plus myelin basic protein 91-103 peptide prevents the development of inflammatory lesions characteristic of experimental allergic encephalomyelitis. Thus, treatment with MHC-self-peptide complexes could serve as a highly specific therapeutic modality in treating autoimmune disease when the putative autoantigen and the MHC restricting elements are known.
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PMID:Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes. 172 35

Two autoimmune disease models were studied in rhesus monkeys: type II collagen-induced arthritis (CIA) and experimental allergic encephalomyelitis (EAE). Unrelated outbred animals were used in these studies. In both models disease resistant and susceptible individuals could be identified. Susceptibility correlated with in vitro cellular responsiveness to antigen in the CIA model. In both models resistant as well as susceptible individuals developed a humoral response to the inducing antigen. However, there is an indication that IgM antibodies play a crucial role in the induction of CIA. No clear association between major histocompatibility complex (MHC) type and disease incidence was found although a higher frequency of a certain DR type was observed in EAE susceptible monkeys. It is likely that both the antigen binding capacity of the MHC class II molecules and the T-cell repertoire play an important role in determining whether disease will develop or not.
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PMID:Autoimmunity in non-human primates: the role of major histocompatibility complex and T cells, and implications for therapy. 177 94

Recent advances in understanding antigen recognition at the level of the trimolecular complex have provided new approaches for selective immunotherapy. Many of these approaches have been applied successfully to the animal model experimental autoimmune encephalomyelitis, and some are being tested in the human disease multiple sclerosis. In addition, new approaches utilizing nonspecific modulation of immune function are being explored in animals and humans. Immunospecific therapy in autoimmune diseases will ultimately be based on understanding how the normal immune system maintains unresponsiveness to self and how this state of self-tolerance is broken. Strategies for specific immune intervention in human diseases based on components of the trimolecular complex will have to take into account the polymorphism of the major histocompatibility complex in humans and the degree of heterogeneity among autoimmune T cells that react with an autoantigen.
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PMID:Tolerance and suppressor mechanisms in experimental autoimmune encephalomyelitis: implications for immunotherapy of human autoimmune diseases. 186 80

There is evidence that the cytokine tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-alpha exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-alpha expression from astrocytes induced by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), and interleukin 1 beta (IL-1 beta). Astrocytes secrete TNF-alpha in response to LPS alone, and can be primed by IFN-gamma to enhance LPS-induced TNF-alpha production. IFN-gamma and IL-1 beta, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-alpha production alone, but act synergistically to stimulate astrocyte TNF-alpha expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-alpha gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-alpha mRNA and protein in response to LPS alone, yet IFN-gamma does not significantly enhance LPS-induced TNF-alpha expression, nor do they express appreciable TNF-alpha in response to the combined stimuli of IFN-gamma/IL-1 beta. In contrast, astrocytes from Lewis rats express low levels of TNF-alpha mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-gamma for subsequent TNF-alpha gene expression. Also, Lewis astrocytes produce TNF-alpha in response to IFN-gamma/IL-1 beta. The differential TNF-alpha production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-alpha expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-gamma, and IL-1 beta in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-gamma priming signals for subsequent TNF-alpha production, suggesting that differential TNF-alpha expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-alpha gene expression in response to LPS and IFN-gamma is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains. 190 Oct 78

Encephalitogenic T cells appear capable of destroying class II major histocompatibility complex (MHC) antigen (Ia)-positive glial cells in the brain, thus accounting for the pathologic activity of these lymphocytes in experimental autoimmune encephalomyelitis (EAE). However, glial cells do not generally express Ia molecules, suggesting that regulation of Ia expression figures prominently in autoimmune diseases of the central nervous system. In studies to understand the regulatory mechanisms involved in Ia expression, a glial cell clone generated from the brains of neonatal Lewis rats (F10 clone) readily expressed class II major histocompatibility (Ia) antigens after stimulation by interferon-gamma (IFN-gamma) at doses from 10 to 100 units/ml. Level of the antigen decreased gradually within 5-7 days after cultures were depleted of the cytokine. Reexposure of the cells to the IFN-gamma at 100-fold lower doses induced a stronger Ia response than did the initial exposure. F10 cells also expressed Ia when they were cultured with small numbers of syngeneic T lymphocytes, either proliferating or nonproliferating. Proliferating T cells had direct Ia-inducing activity, whereas nonproliferating T cells had this effect only when they were added to cultures with small amounts of T cell-specific antigen. Moreover, Ia-inducing effects of IFN-gamma on F10 cells were also greatly enhanced when these cells were preexposured to T cells. Our results suggest that initial exposure to IFN-gamma or T cells enhances the Ia responsiveness of glial cells to further stimulation with the cytokine.
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PMID:Enhanced interferon-gamma-induced Ia-antigen expression by glial cells after previous exposure to this cytokine. 191 26


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