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)

Intravenous treatment of Lewis rats with neuroantigen-coupled splenocytes 7 days before the induction of experimental autoimmune encephalomyelitis with guinea pig myelin basic protein (GP-MBP) resulted in a significant reduction of both the incidence and severity of clinical disease. To test the epitope and functional specificities of the unresponsiveness, splenocytes (SP) coupled with the major encephalitogenic MBP determinant, GP-68-86, were compared with those coupled with intact GP-MBP for the ability to down-regulate clinical disease and Ag-specific T cell responses (proliferation, cytokine production, and delayed-type hypersensitivity) in animals primed with either intact GP-MBP/CFA or GP-68-86/CFA. GP-MBP-SP and GP-68-86-SP were equally efficient at significantly inhibiting clinical disease in animals primed with GP-68-86/CFA. In contrast, tolerization with intact GP-MBP-SP was significantly more efficient than that with GP-68-86-SP at reducing disease incidence and severity in GP-MBP/CFA-primed animals, which indicates a role for secondary (cryptic) encephalitogenic epitopes in GP-MBP-induced disease. By testing a panel of GP-68-86 peptides that contained conservative amino acid substitutions at either position 75 (A75) or 80 (P80) or at both, residues that previously had been shown to be TCR contact residues, for their ability to inhibit experimental autoimmune encephalomyelitis induction, were assessed for the fine specificity of tolerance induction. None of the substituted peptides were capable of affecting the course of paralytic disease that had been induced by sensitization with the native GP-68-86 epitope, but all significantly reduced a milder form of the disease that had been produced by priming with the (A75,P80) 68-86 substituted peptide. With regard to the functional specificity of tolerance induction, lymph node T cells derived from either GP-MBP-SP- or GP-68-86-SP-treated animals exhibited a marked reduction in both proliferation and production of Th1-derived cytokines (IL-2, IFN-gamma, and lymphotoxin/TNF-alpha) in response to either GP-MBP or GP-68-86 in culture. In contrast, no consistent significant differences in delayed-type hypersensitivity responses were observed in any of the experimental groups relative to controls. Histologic examination of central nervous system tissues from the tolerant and control groups revealed significantly reduced, but still demonstrable, levels of perivascular infiltration even in asymptomatic animals.
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PMID:Epitope and functional specificity of peripheral tolerance induction in experimental autoimmune encephalomyelitis in adult Lewis rats. 751 25

Oral administration of myelin basic protein (MBP) is an effective means of suppressing experimental autoimmune encephalomyelitis (EAE). In the Lewis rat model, we have previously shown that this effect is mediated by active suppression as T lymphocytes from animals orally tolerized to MBP suppress in vitro immune responses and in vivo adoptively transfer disease protection to naive recipients. This effect is mediated by the cytokine TGF-beta which is secreted by T cells from orally tolerized animals after being triggered by the oral tolerogen. In the present study we investigated Peyer's patches in SJL mice following orally administered MBP. Peyer's patches are one of the major lymphoid structures of gut-associated lymphoid tissue, and a site thought to play an important role in the induction of oral tolerance. Twenty-four hours after one feeding of 1 mg of MBP, there were no proliferative responses to MBP in Peyer's patches. However, when Peyer's patches from MBP-fed animals were stimulated with IL-2 in the presence of MBP, reduced proliferation to IL-2 was observed, and this inhibition was reversed with anti-TGF-beta antibody. Suppression of IL-2-induced proliferation by MBP was not observed in unfed animals or if Peyer's patches from MBP-fed animals were stimulated with a control antigen (ovalbumin). Stimulation of Peyer's patches T cells from MBP-fed animals with MBP resulted in secretion of TGF-beta in a dose-related fashion with less TGF-beta secretion at higher doses. Furthermore, cells from Peyer's patches of animals fed MBP adoptively transferred protection to actively induced EAE. Thus, MBP-specific TGF-beta-secreting regulatory cells recovered from Peyer's patches after a single oral administration of MBP are not evident as measured by proliferation, but are capable of suppressing in vitro and in vivo cell-mediated immune responses. Peyer's patches appear to be an important site for the induction of cells which mediate the active suppression component of oral tolerance.
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PMID:Oral tolerance to myelin basic protein induces regulatory TGF-beta-secreting T cells in Peyer's patches of SJL mice. 752 Aug 38

TCR peptides, namely V beta 8.2-39-59 or the minimal idiotope, V beta 8-44-54, can treat experimental autoimmune encephalomyelitis (EAE) in Lewis rats, presumably by activating naturally induced TCR peptide-specific T cells that arise in response to the focused appearance of V beta 8.2+ encephalitogenic T cells. The purpose of the present study was to evaluate the mechanisms by which TCR peptides inhibit EAE. We found that treatment of EAE with the V beta 8.2-39-59 peptide did not induce any evidence of DNA fragmentation (apoptosis) in spinal cord cells isolated from clinically well rats, implicating a regulatory rather than a deletional mechanism. TCR peptide-specific T cell lines failed to inhibit EAE induced by already activated BP-specific T cells when the two T cell specificities were co-injected. However, coculturing the encephalitogenic T cells in the presence of the regulatory T cells during the activation step before transfer almost completely inhibited the induction of EAE. Inhibition could be induced by direct contact between the two cell types or by soluble factors produced in a transwell system, but was greatly enhanced when soluble V beta 8.2-39-59 peptide was used to optimally activate the regulatory T cells. The inhibition was regulatory cell dose dependent, and was reflected in vitro by reduced proliferation response and mRNA production for IL-3, and to a lesser extent, IFN-gamma and IL-2. These results indicate that regulation induced by TCR peptides involves cell-cell interactions that lead to the production and release of soluble factors that locally inhibit the activation of encephalitogenic T cells expressing MHC-bound idiotopes of the target V beta-chain, and possibly "bystander" specificities expressing different V beta-chains.
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PMID:Coculture of TCR peptide-specific T cells with basic protein-specific T cells inhibits proliferation, IL-3 mRNA, and transfer of experimental autoimmune encephalomyelitis. 752 21

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

T cell activation requires both Ag/MHC recognition and costimulatory signals. The present studies were designed to test whether the loss of tolerance to myelin basic protein (MBP) requires costimulation by members of the B7 receptor family. CTLA-4Ig, a fusion protein ligand for B7-1 and B7-2, was used to assess the role of B7-mediated costimulation in chronic relapsing experimental allergic encephalomyelitis (EAE) induced by the transfer of MBP specific T cell lines. In adoptively transferred EAE, administering CTLA-4Ig to donor mice or during in vitro activation of MBP specific-T cells resulted in diminution of clinical disease. The presence of CTLA-4Ig during both the immunization and in vitro activation stages was most effective in preventing clinical signs of disease. This diminution in clinical disease was paralleled by a decreased proliferative response and reduced production of IL-2 and IL-4, but not IFN-gamma, after antigenic stimulation of encephalitogenic T cells in vitro. In contrast, CTLA-4Ig treatment of recipient animals after the transfer of MBP-activated T cells affected neither disease course nor severity. These results indicate that additional costimulatory pathways may be involved in established EAE, or that some cells are independent of costimulation or, alternatively, that CTLA-4Ig does not enter brain parenchyma in therapeutic concentrations. Thus, we conclude that costimulation provided by B7 molecules plays a major role in the development of encephalitogenic T cells and in the establishment of chronic relapsing EAE, a prototypic CD4+ T cell-mediated autoimmune disease.
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PMID:Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. 752 5

Remission of experimental autoimmune encephalomyelitis (EAE) in Lewis rats may involve mediators such as prostaglandins (PG) that are produced within demyelinating lesions and are known to potently inhibit T cell responses. In support, this study shows that PGE2 inhibited myelin basic protein (MBP)-specific responses of proliferation and IL-2 production by continuously propagated lines of T-helper cells. Simultaneous exposure to PGE2 and immunogenic MBP rendered T cells profoundly anergic. Even after several weeks of propagation in IL-2-containing medium, anergic T cells exhibited marked reductions in MBP-stimulated proliferation and IL-2 production responses when restimulated with optimal concentrations of MBP and irradiated splenocytes (SPL). PGE2 did not block other measures of MBP-dependent activation, including induction of postactivation refractoriness in IL-2 production pathways, activation-dependent decreases in MBP reactivity, and activation-dependent increases in PGE2 sensitivity. Proliferative responses by anergic T cells were reduced in magnitude but were not altered in their sensitivity to MBP. PGE2-mediated anergy was manifest as an intrinsic deficit rather than an acquired suppressive activity and was associated with reduced mitogenic responsiveness and a block in IL-2 production pathways. Anergic T cells were responsive to IL-2 and eventually regained full antigenic reactivity after extended propagation in IL-2-supplemented medium. In summary, a limited exposure to PG had long-lasting inhibitory effects on subsequent T cell responsiveness to the target autoantigen MBP. These findings support the hypothesis that PG may promote disease remission by inducing anergy in helper T cells.
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PMID:Prostaglandin E2 promotes the induction of anergy during T helper cell recognition of myelin basic protein. 753 Nov 17

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by the i.v. injection of 10(7) cloned V beta 8.2+ T cells specific for the 72-89 peptide of guinea pig myelin basic protein (MBP). Some animals were injected simultaneously with 10(7) cloned T cells specific for ovalbumin (OVA). Lymphocytes were isolated from the spinal cord and from the peripheral lymphoid organs of these rats and the frequencies of MBP-peptide-specific or OVA-specific proliferating cells were estimated by limiting dilution analysis at different times after cell transfer. The frequencies of cells specific for MBP72-89 or OVA in the spinal cord were highest 5 days after cell transfer (MBP72-89, 1 in 1149; OVA, 1 in 1116). On day 7, when the rats were recovering, the frequency of cells specific for MBP72-89 in the spinal cord fell dramatically to < 1 in 10(5), while that of OVA-specific cells decreased to a much lesser extent (1 in 7001). The frequencies of MBP72-89-specific cells in the peripheral lymphoid organs during and after recovery were also much lower than those of OVA-specific cells. A similar pattern of down-regulation of the MBP-peptide-specific, but not the OVA-specific, T cell response was observed in the spleen and mesenteric lymph nodes (MLN) of rats 38 days after the active induction of EAE by immunization with equal amounts of MBP and OVA in adjuvants. In the passively transferred model, cells isolated from the spinal cord and MLN on day 7 did not regain responsiveness to MBP72-89 after incubation with high levels of IL-2, indicating that the unresponsiveness was not due to T cell anergy. Thus this study demonstrates that there is a specific down-regulation of the MBP72-89-specific T cell response during spontaneous recovery from EAE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antigen-specific down-regulation of myelin basic protein-reactive T cells during spontaneous recovery from experimental autoimmune encephalomyelitis: further evidence of apoptotic deletion of autoreactive T cells in the central nervous system. 757 5

We studied the contribution of the CD28-B7 costimulatory T cell activation pathway to the pathogenesis of experimental autoimmune encephalomyelitis in the Lewis rat model. Systemic administration of CTLA4Ig suppressed clinical disease and was effective even when CTLA4Ig was delayed until day 10 postimmunization, a time when pathologic disease is evident. This protection was not reversible by systemic administration of high doses of IL-2. Detailed immunohistologic studies showed that CTLA4Ig therapy resulted in suppression of the inflammatory response with inhibition of Th1 (IL-2 and IFN-gamma) and sparing of Th2 (IL-4, IL-10, and IL-13) cytokines in the central nervous system. These results indicate that the CD28-B7 T cell costimulatory pathway plays an important role in experimental autoimmune encephalomyelitis, a Th1-mediated disease, and suggest that blockade of this costimulatory pathway protects against active disease by causing a state of immune deviation towards Th2 function. The ability of CTLA4Ig to treat animals with pathologically established disease may have important clinical implications for patients with multiple sclerosis.
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PMID:CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spares Th2 cytokines in the central nervous system. 759 47

The phenotypic and functional characteristics of activated T cells and recruited unactivated T cells at an inflammatory site were examined using a V beta 4+ myelin basic protein-specific T cell clone in a passively transferred model of experimental allergic encephalomyelitis. A high percentage of the T cells isolated from the central nervous system (CNS) were V beta 4+. This population exhibited the characteristics of activated T cells based on the proportion of cells in the blast state, their ability to proliferate in response to IL-2 or CNS Ag, and their expression of activation/memory cell markers. Activated V beta 4+ T cells were also observed in the periphery. Large numbers of V beta 4- T cells, which are entirely host-recruited, were also found in the CNS, where they demonstrated the properties of memory cells. There were differences in adhesion molecule expression between CNS V beta 4+ T cells and peripheral V beta 4+ T cells, although both populations were in activated state. V beta 4+ T cells at the site of Ag expression (the spinal cord) demonstrated higher levels of LFA-1 and CD44, but lower levels of VLA-4 and intercellular adhesion molecule-1, than did V beta 4+ T cells in the spleen. In contrast, the levels of all of these adhesion molecules on recruited V beta 4- T cells were higher in the CNS than in the periphery. This experimental model allows the detailed characterization of different T cell populations isolated from the same inflammatory site.
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PMID:Presence of T cells with activated and memory phenotypes in inflammatory spinal cord lesions. 759 58

Experimental autoimmune uveoretinitis (EAU) was induced in Lewis rats and the inflamed retinas were examined for IFN-gamma, IL-2, IL-4, and IL-10 mRNA production at serial time points using the reverse transcriptase-polymerase chain reaction. IFN-gamma, IL-2, IL-4, and IL-10 mRNAs were all detected 24 hr before the earliest time point at which histological changes have previously been detected. IFN-gamma, IL-2, and IL-4 mRNA expression peaked during the active phase of the disease and declined in parallel with lymphocyte numbers as the inflammation resolved. IL-10 mRNA levels increased more slowly, reaching a maximum at later stages of disease. The observed pattern of cytokine mRNA expression in the retina in EAU is similar to that reported in experimental autoimmune encephalomyelitis (EAE). The increase in IL-10 mRNA expression in late disease may reflect a role in disease resolution as previously proposed in EAE.
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PMID:The kinetics of cytokine mRNA expression in the retina during experimental autoimmune uveoretinitis. 763 45


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