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)

Targeting peptides have potential as components of recombinant vaccines. Here, we have analyzed a set of structurally diverse peptides fused to a polyepitope vaccine in prevention of rat generalized autoimmunity of the nervous system (GANS), a combined model of experimental autoimmune encephalomyelitis (EAE), neuritis (EAN) and uveoretinitis (EAU). The peptide sequences studied included the endothelial-monocyte-activating polypeptide II (EMAP II), the allograft inflammatory factor-1 (AIF-1), and the interferon-gamma-inducing factor (IGIF, IL-18). Further, a variety of adhesive peptides were tested, including the disintegrin domain of mouse ADAM 8. Interestingly, this disintegrin domain considerably increased the effect of the polyepitope vaccine. Of the other peptides, only IL-18 enhanced tolerance induction, but was less effective than the ADAM 8 disintegrin peptide. In conclusion, disintegrin domains will be valuable leads in the development of targeting peptides for immunointervention.
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PMID:The disintegrin domain of ADAM 8 enhances protection against rat experimental autoimmune encephalomyelitis, neuritis and uveitis by a polyvalent autoantigen vaccine. 967 Aug 63

Experimental autoimmune encephalomyelitis (EAE) is a model of autoimmune central nervous system (CNS) disease that is mediated by autoreactive Th1 cells secreting the proinflammatory cytokine interferon (IFN)-gamma. Interleukin (IL)-12 in its heterodimeric p35/p40 isoform and the recently described cytokine IL-18 potently induce T cell production of IFN-gamma. Interleukin-1beta converting enzyme (ICE) is required to convert IL-18 precursor protein into its biologically active mature form. In this study, we used semiquantitative reverse transciptase-polymerase chain reaction to determine steady state levels of IL-12, IL-18, and ICE mRNA in the spinal cord of Lewis rats at different stages of EAE. In control rats, we found significant IL-18, ICE, and IL-12p35, but not IL-12p40 mRNA expression. IL-18 mRNA increased during the acute stage of EAE together with a marked induction of ICE mRNA. IL-12p35 mRNA levels did not change significantly throughout the course of EAE. Surprisingly, the peak expression of IL-12p40 mRNA was delayed by several days relative to the peak of T cell infiltration and IFN-gamma mRNA synthesis. Our data implicate the IL-18/ICE pathway in the amplification of Th1-mediated immune responses in the CNS but suggest a different, so far undefined role of endogenous IL-12 in the late effector phase of EAE.
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PMID:Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat. 984 24

T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1beta-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1beta and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the clinical course and transcription rate of proinflammatory cytokines such as TNF-alpha, IL-1beta, IFN-gamma, and IL-6. A reduction of EAE incidence and severity is observed in caspase-1-deficient mice, depending on the immunogenicity and on the amount of the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incidence correlates with defective development of anti-MOG IFN-gamma-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord homogenate or MOG35-55 peptide, by the caspase-1-inhibitor Z-Val-Ala-dl -Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These results indicate that caspase-1 plays an important role in the early stage of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS.
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PMID:Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. 1045 74

Integral immunohistochemical analysis of immune responses in frozen sections requires that, in addition to constitutively expressed membrane CD markers, less stable determinants can be reliably visualized. Therefore, we compared the commonly used acetone fixation method with pararosaniline fixation for six determinant categories. These categories included selected constitutively expressed markers, inducible co-stimulatory molecules, pro- and anti-inflammatory cytokines (including the novel cytokine IL-18, also known as IGIF and IL-1gamma), antigen-specific antibody in plasma cells, bacterial peptidoglycan, and lysosomal acid phosphatase activity. Human spleen and mouse spleen activated by agonistic anti-CD40 antibody or TNP-Ficoll immunization were analyzed in parallel with brain tissue from multiple sclerosis (MS) patients and marmoset monkeys with experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Fixation with pararosaniline resulted in better morphology of all tissues and inhibited endogenous alkaline phosphatase activity in brain tissue. Most determinants could be reliably detected. Staining sensitivity and intensity were markedly increased for selected determinant-tissue combinations, e.g., for IL-4 in human spleen and CD40 in human and mouse spleen. These data show that pararosaniline is a useful alternative to acetone, resulting in superior morphology and specific staining for selected determinant-tissue combinations. This provides additional flexibility for in situ analysis of immune reactivity.
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PMID:Pararosaniline fixation for detection of co-stimulatory molecules, cytokines, and specific antibody. 1065 90

Experimental Allergic Encephalomyelitis (EAE) is a demyelinating disease of the central nervous system which is an animal model for the human autoimmune disease, multiple sclerosis. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 cytokines. IL-12 produced by monocytes and dendritic cells is the most critical factor which influences the development and differentiation of pathogenic autoreactive Th1 cells. Here, we review our recent studies on the critical contributions of IL-12 and the IL-12R beta 2 subunit to the generation of autoreactive effector cells which mediate EAE. In addition, we discuss the potential contribution of IL-18 to the upregulation of the IL-12/IL-12R beta 2 pathway and the contribution of the suppressor cytokines, IL-4 and IL-10, in downregulating this pathway. Collectively, our studies demonstrate that the IL-12/IL-12R beta 2 pathway is a critical intermediary in the process of Th1 differentiation which can be both positively or negatively regulated. This pathway remains an attractive immunotherapeutic target for blockade of function with inhibitory reagents or downregulation by Th2 cytokines.
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PMID:The critical role of IL-12 and the IL-12R beta 2 subunit in the generation of pathogenic autoreactive Th1 cells. 1066 72

Cytokines orchestrate T cell-mediated immune responses. In experimental autoimmune encephalomyelitis (EAE) the proinflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-12 and IL-18 are critically involved in the initiation and amplification of the local immune response in the CNS which is counter-balanced by upregulation of antiinflammatory cytokines such as IL-10. The predicted function of individual cytokines during EAE has recently been challenged by transgenic animal studies and neutralization experiments. Cytokine induction is not restricted to autoimmunity in the nervous system. Cytokines are involved in nerve regeneration and induced in focal cerebral ischemia both at the site of infarction and in remote nonischemic brain regions. In cerebral ischemia TNF-alpha and IL-1beta probably have dual functions: In concert with upregulation of inducible NO synthase (iNOS) they exert neurotoxicity while in the absence of iNOS, TNF-alpha and IL-1beta may contribute to neuroprotection and plasticity. The interplay between glial cells, infiltrating leukocytes and induced cytokines leading to CNS pathology is complex and incompletely understood. Further assessment of the functional contribution of cytokines critically depends on the elucidation of downstream secondary signaling mechanisms.
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PMID:Cytokines in CNS disorders: neurotoxicity versus neuroprotection. 1096 21

IL-18 promotes NK cell and Th1 cell activity and may bridge innate and adaptive immune responses. Myelin oligodendrocyte glycoprotein (MOG) is a myelin component of the CNS and is a candidate autoantigen in multiple sclerosis. In the present study we show that IL-18-deficient (IL-18-/-) mice are defective in mounting autoreactive Th1 and autoantibody responses and are resistant to MOG35-55 peptide-induced autoimmune encephalomyelitis. IL-18 administration enhances the disease severity in wild-type mice and restores the ability to generate Th1 response in the IL-18-/- mice. This restoration was abrogated in NK cell-depleted mice, indicating that the action of IL-18 in promoting the generation of MOG-specific Th cells was dependent on NK cells. Furthermore, transfer of NK cells from recombinase-activating gene 1-/- mice, but not from recombinase-activating gene 1/IFN-gamma-/- mice, rescued the defective Th1 responses in IL-18-/- mice and rendered IL-18-/- mice susceptible to the induction of autoimmune encephalomyelitis. Thus, IL-18 can direct autoreactive T cells and promote autodestruction in the CNS at least in part via induction of IFN-gamma by NK cells.
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PMID:IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-gamma by NK cells. 1097 22

Microglia are resident central nervous system (CNS) macrophages. Theiler's murine encephalomyelitis virus (TMEV) infection of SJL/J mice causes persistent infection of CNS microglia, leading to the development of a chronic-progressive CD4(+) T-cell-mediated autoimmune demyelinating disease. We asked if TMEV infection of microglia activates their innate immune functions and/or activates their ability to serve as antigen-presenting cells for activation of T-cell responses to virus and endogenous myelin epitopes. The results indicate that microglia lines can be persistently infected with TMEV and that infection significantly upregulates the expression of cytokines involved in innate immunity (tumor necrosis factor alpha, interleukin-6 [IL-6], IL-18, and, most importantly, type I interferons) along with upregulation of major histocompatibility complex class II, IL-12, and various costimulatory molecules (B7-1, B7-2, CD40, and ICAM-1). Most significantly, TMEV-infected microglia were able to efficiently process and present both endogenous virus epitopes and exogenous myelin epitopes to inflammatory CD4(+) Th1 cells. Thus, TMEV infection of microglia activates these cells to initiate an innate immune response which may lead to the activation of naive and memory virus- and myelin-specific adaptive immune responses within the CNS.
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PMID:Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virus. 1155 11

The aim of this study was to identify immune-related genes affected by treatment with 17beta-estradiol (17beta-E2) that contribute to protection of T cell antigen receptor double transgenic mice from experimental autoimmune encephalomyelitis (EAE). The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated mice protected from EAE vs. control mice with severe EAE. In general, E2 treatment affected about 10% of the genes tested, but only 18 cytokine, chemokine/receptor, adhesion molecule, or activation genes were up- or down-regulated more than 2.4-fold by E2 treatment. Down-regulated genes included TNFalpha (an important proinflammatory cytokine in EAE); peptidoglycan recognition proteins (Pgrp); regulated on activation, normal T cell expressed and secreted (RANTES); and neural cell adhesion molecule (MCP-1). Up-regulated genes included cytotoxic T lymphocyte antigen-4 (CTLA-4; known to inhibit T cell activation), TGFbeta3, IL-18, and two interferon-gamma-induced genes, the chemokines: monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), vascular cell adhesion molecule (VCAM), and disintegrin metalloprotease (thought to regulate TNFalpha production). These results implicate a limited set of known and previously unsuspected E2-sensitive genes that may be crucial for inhibition of EAE and potentially the human disease, multiple sclerosis.
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PMID:Evaluation of the effects of 17beta-estradiol (17beta-e2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray. 1175 23

IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
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PMID:Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. 1257 88


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