Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Epitope and functional specificity of peripheral tolerance induction in experimental autoimmune encephalomyelitis in adult Lewis rats. 751 25

A combined role of a virus infection of the central nervous system (CNS) and an autoimmune response to myelin basic protein (MBP), an autoantigen of the CNS, is suggested in the pathogenesis of multiple sclerosis (MS). SJL mice are highly susceptible while B6 mice are less susceptible to the induction of experimental autoimmune encephalomyelitis (EAE), the autoimmune model of MS. Peripheral inoculation of Semliki forest virus (SFV) into SJL and B6 mice resulted in: (1) Higher viral titers, more severe clinical disease, and hence a stronger nonspecific and SFV-specific lymphoproliferation, and production of IFN-gamma and TNF/LT was observed by splenocytes (SPL) of B6 than by those of SJL mice, on Day 7 postinfection. (2) Following viral clearance, however, proliferation to SFV, and to MBP, and the production of IFN-gamma and TNF/LT by SPL of SFV-infected SJL mice were significantly higher, while the production of TGF-beta was significantly lower than by those of B6 mice. In conclusion, the immune responses to SFV, and to MBP, which were triggered by SFV infection were significantly higher and more prolonged in the SPL of SJL mice, the EAE-susceptible mice, than by those of B6 mice after the infection was cleared.
 ...
PMID:Immune responses, and autoimmune outcome, during virus infection of the central nervous system. 751 51

Experimental autoimmune encephalomyelitis (EAE) is influenced by polymorphism of the MHC. We have previously found that Lewis rats with certain MHC haplotypes are susceptible to disease induced with the myelin basic protein (MBP) peptide 63-88, whereas Lewis rats with other MHC haplotypes are resistant. Interestingly, rats with the MHC u haplotype develop an immune response to the MBP 63-88, but do not get EAE. In this study we have used intra-MHC recombinant rat strains to compare the influences of the MHC u with the a haplotype. We discovered the following: 1) The class II region of the MHC a haplotype permits EAE and a Th1 type of immune response as measured by IFN-gamma production after in vitro challenge of in vivo-primed T cells with MBP 63-88. 2) The class II region of the u haplotype is associated with a disease-protective immune response characterized by production of not only IFN-gamma, but also of IL-4 mRNA expression by the MBP 63-88-activated cells. 3) The class I region upstream of the class II region of the u haplotype is associated with a disease-protective effect and the expression of mRNA for TGF-beta after MBP 63-88-induced activation. Thus, such a TGF-beta response occurs in all strains expressing the class I Au allele. Treatment with Abs to CD8+ cells abrogates peptide-induced TGF-beta mRNA expression, and aggravates disease in strains with the class I Au allele.
 ...
PMID:Protective influences on experimental autoimmune encephalomyelitis by MHC class I and class II alleles. 752 59

The intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible strains of mice results in a chronic, immune-mediated demyelinating disease that shares many features with human multiple sclerosis. As with human MS, T lymphocytes seem to be critically important for the pathogenesis of this virally induced, demyelinating disease. Therefore, determining the fine specificity of the T cell response may be essential for elucidating the mechanism(s) involved in demyelination. By using fusion proteins and synthetic peptides, we have initially identified a region within the amino acid residues 233 to 250 of the VP1 capsid protein of Theiler's virus that is recognized by T cells from either TMEV-immunized or TMEV-infected, demyelination-susceptible SJL/J mice. A T lymphocyte precursor frequency analysis indicates that a major TMEV-reactive T cell population in the periphery of virus-infected mice recognizes this VP1 region. The fine epitope specificity has been further determined to be within VP1(233-244) using additional synthetic peptides. VP1(233-244)-specific T cells seem to represent a significant population of TMEV-reactive T lymphocytes within the demyelinating lesions, because such T cells have been cloned from the spinal cords of infected mice. Interestingly, all TMEV-specific T cell clones derived from the demyelinating lesions, regardless of epitope specificity, produce IFN-gamma on stimulation and thus may play a critical role in the recruitment and activation of inflammatory cells leading to demyelination. Taken together, these data suggest that a T cell response against VP1(233-244) is involved in the pathogenesis of TMEV-induced demyelinating disease.
 ...
PMID:A predominant viral epitope recognized by T cells from the periphery and demyelinating lesions of SJL/J mice infected with Theiler's virus is located within VP1(233-244). 752 7

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.
 ...
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

An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complementary determining region of the T cell receptor (TCR) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87-99, class II major histocompatibility complex (MHC), and TCR, and designed soluble inhibitors for therapy. F, N, I, and V at positions 90, 92, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCR. The peptides, p87-99[95T > A] and p87-99[96P > A] could compete more effectively with p87-99 for binding to MHC and could antagonize the in vitro response to T cells to p87-99 more effectively than p87-99[91K > A]. However, only p87-99[91K > A] prevented and reversed EAE, indicating that the extent of MHC or TCR competition does not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antagonists were challenged in vitro with p87-99. Administration of p87-99[91K > A], but not p87-99 [95T > A] or p87-99[96P > A], reduced the production of tumor necrosis factor (TNF)- alpha and interferon (IFN) gamma. IFN-gamma and TNF-alpha are two cytokines that are critical in the pathogenesis of EAE and MS.
 ...
PMID:Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. 752 50

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.
 ...
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.
 ...
PMID:Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. 752 5

Astrocytes in the central nervous system (CNS) associate intimately with vascular endothelial cells and are integral to the blood-brain barrier (BBB). Leukocyte transmigration across the BBB is a cardinal feature of CNS inflammation, as observed in experimental autoimmune encephalomyelitis, and very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1) interactions have recently been proposed as essential for this process. VCAM-1 expression by astrocytes was recently reported. We addressed the regulation of VCAM-1 expression by inflammatory cytokines in primary human astrocytes and two human astrocytoma cell lines. Astrocytoma cells up-regulated surface VCAM-1 expression in response to cytokines in the following order: IFN-gamma plus TNF-alpha > IFN-gamma plus IL-1 beta > TNF-alpha > IFN-gamma. Cytokine-activated astrocytoma cells expressed 7-domain VCAM-1, as indicated by accumulation of 3.2-kb VCAM-1 mRNA and immunoprecipitation of a 100-kDa protein with anti-VCAM-1 mAb. Lymphoblast adhesion to cytokine-activated astrocytoma cell monolayers was significantly blocked by mAb specific for VCAM-1 and VLA-4, indicating that astrocytoma cell VCAM-1 was functional. Astrocytoma cell expression of VCAM-1 could be a constituent of the astrocyte phenotype. To support this possibility, we demonstrated that cytokine-treated adult human and rat primary astrocytes expressed VCAM-1, and the rank order of cytokine potency for VCAM-1 induction in primary and neoplastic astrocytes was strikingly similar. This is the first documentation of VCAM-1 expression by adult human astrocytes. Expression of VCAM-1 by astrocytes at the BBB could play a role in mononuclear leukocyte entry into the CNS.
 ...
PMID:Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines. 753 Jul 45

We have previously shown that orally administered myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis in both the Lewis rat and the SJL mouse. In the Lewis rat fed low doses of MBP, we found that protection can be adoptively transferred by CD8+ cells and that these cells inhibit immune responses via the secretion of TGF-beta after Ag-specific triggering. In the present study, we investigated the cellular requirements for the generation of active suppression following oral administration of MBP in SJL and (PLJ x SJL)F1 mice. We first determined the frequency of MBP cells secreting Th1 (IFN-gamma) and Th2 (IL-4/IL-10) cytokines or TGF-beta after oral administration of MBP. We found that in SJL mice, orally administered MBP (0.5 mg/feeding) led to an increased frequency of TGF-beta-, IL-4-, and IL-10-secreting cells and a decreased frequency of IFN-gamma-producing cells. This pattern was observed in both CD4+ and CD8+ populations; adoptive transfer of either CD4+ or CD8+ cells from orally tolerized mice suppressed autoimmune encephalomyelitis in recipient animals. We then studied the role of CD8+ cells on the generation of oral tolerance to MBP by depleting CD8+ cells in vivo with anti-CD8 mAb. Oral tolerance was successfully induced in such animals, as demonstrated by a decrease in clinical disease and T cell proliferative responses, although there was less TGF-beta production in vitro and less disease protection on days 20 to 22 in CD8-depleted animals. These studies demonstrate that CD4+ cells in the absence of CD8+ cells can mediate the active suppression component of oral tolerance in mice and that there is a reciprocal relationship between Th1- and Th2-type cytokine production associated with oral tolerization.
 ...
PMID:Induction of oral tolerance to myelin basic protein in CD8-depleted mice: both CD4+ and CD8+ cells mediate active suppression. 754 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>