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)

Experimental allergic encephalomyelitis is a prototypic autoimmune disease characterized by central nervous system inflammation and demyelination. Previously, we demonstrated that intravenous administration of high doses of myelin basic protein abrogated the clinical and pathological signs of experimental allergic encephalomyelitis by causing the deletion of encephalitogenic, CD4+, myelin basic protein-specific T cells through antigen-induced programmed cell death. In the present study, we further characterized the ability of intravenous antigen administration to attenuate an immune response by myelin basic protein-reactive encephalitogenic T cells. We demonstrated that multiple injections of myelin basic protein are required to achieve a therapeutic response, and that this form of therapy is effective even after prolonged chronic disease. These studies showed that although interleukin-2-stimulated cell cycling is an important factor leading to T-cell death, the administration of exogenous interleukin-2 with antigen can result in the aggravation of clinical disease compared to administration of antigen alone. More importantly, administration of myelin basic protein alone without interleukin-2 was sufficient to reduce autoreactive T cells and clinical disease in experimental autoimmune encephalomyelitis. Our experiments support the rationale for antigen-specific therapy aimed at inducing the programmed death of autoreactive T cells in autoimmune diseases, potentially including the human demyelinating disease multiple sclerosis.
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PMID:Intravenous antigen administration as a therapy for autoimmune demyelinating disease. 857 66

A variable region gene of the T-cell receptor, V beta 8.2, is rearranged, and its product is expressed on pathogenic T cells that induce experimental autoimmune encephalomyelitis (EAE) in H-2u mice after immunization with myelin basic protein (MBP). Vaccination of these mice with naked DNA encoding V beta 8.2 protected mice from EAE. Analysis of T cells reacting to the pathogenic portion of the MBP molecule indicated that in the vaccinated mice there was a reduction in the Th1 cytokines interleukin-2 (IL-2) and interferon-gama. In parallel, there was an elevation in the production of IL-4, a Th2 cytokine associated with suppression of disease. A novel feature of DNA immunization for autoimmune disease, reversal of the autoimmune response from Th1 to Th2, may make this approach attractive for treatment of Th1-mediated diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis.
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PMID:Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. 870 50

We have studied the effects of corticosteroid treatment on the numbers of lymphocytes obtained from the spinal cords of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Flow cytometric studies showed that treatment with dexamethasone (4 mg/kg) 8-12 h prior to study on day 14 after inoculation resulted in a reduction in the numbers of CD5+, TCR alpha beta + and V beta 8.2+ cells in the spinal cord. Limiting dilution analysis indicated that dexamethasone treatment 12 h prior to study on day 12 after inoculation reduced the frequencies of MBP-reactive and interleukin-2-responsive lymphocytes in the spinal cord to low levels, but reduced the frequency of concanavalin-A-responsive lymphocytes to a lesser extent. Using propidium iodide staining of nuclear chromatin we also studied lymphocyte apoptosis. Greater numbers of apoptotic cells were found in the cells extracted from the spinal cords of rats, examined on day 14, that had been treated 1-12 h previously with dexamethasone, than in saline-treated controls. This increased level of apoptosis was observed in the CD5+ and TCR alpha beta + cell populations. At 1-4 h after dexamethasone treatment there was a reduction in the selective apoptosis of V beta 8.2+ cells that normally occurs during spontaneous recovery from EAE. Therefore apoptosis of V beta 8.2+ cells cannot explain the reduction in the numbers of V beta 8.2+ cells and MBP-reactive cells in the CNS after dexamethasone treatment. By 8-12 h after dexamethasone treatment the selectivity of the apoptotic process was restored. These studies suggest that a reduction in the number of T-lymphocytes in the central nervous system contributes to the beneficial effects of corticosteroids in EAE.
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PMID:Corticosteroid treatment of experimental autoimmune encephalomyelitis in the Lewis rat results in loss of V beta 8.2+ and myelin basic protein-reactive cells from the spinal cord, with increased total T-cell apoptosis but reduced apoptosis of V beta 8.2+ cells. 889 17

In vivo administration of interleukin-2 (IL-2)-secreting tumor cells results in complete protection against persistent infection by Theiler's murine encephalomyelitis virus (TMEV) in susceptible DBA/2 mice. The IL-2-mediated protection was found to depend on the inoculum size as well as the timing of IL-2 administration. IL-2-treated and TMEV-infected mice displayed a three- to fourfold relative increase in virus-specific cytotoxic T-lymphocyte (CTL) precursors. Thus, we postulate that the persistence of TMEV infection in susceptible mice reflects limited numbers of relevant CTL precursors and their time course of induction and activation.
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PMID:In vivo administration of interleukin-2 protects susceptible mice from Theiler's virus persistence. 898 19

Myelin basic protein (MBP)-specific T cells are implicated in the pathogenesis of multiple sclerosis and are targets of selective immunotherapies. However, autoantigen-specific T cells can also be isolated from healthy individuals. Their functional potential is unknown and obviously cannot be tested in humans. We approached this question in a closely related primate species, the rhesus monkey. CD4+ T cell lines specific for MBP were isolated from normal rhesus monkeys using the same primary limiting dilution technique that is now widely used to generate human autoreactive T cell clones in vitro. Three different epitopes were recognized by three rhesus T cell lines isolated from three different monkeys. Upon activation, all lines produced interferon-gamma, interleukin-2, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor but neither interleukin-4 nor transforming growth factor-beta. The MBP-specific T cells were injected intravenously without adjuvant into the nonirradiated autologous monkey. One of the three rhesus monkeys developed an encephalomyelitis with a pleocytosis in the spinal fluid and perivascular infiltrates in the leptomeninges, spinal nerve roots and cerebral cortex. The data demonstrate that the normal immune repertoire of a primate species contains MBP-specific CD4+ T cells that are able to induce an autoimmune encephalomyelitis upon transfer into the nonirradiated autologous recipient.
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PMID:Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques. 903 60

Apoptosis is a major mechanism of T cell elimination during ontogeny and tolerance induction as well as in autoimmunity. To assess the possible involvement of reactive oxygen and nitrogen intermediates (ROI and NO.) in T-cell apoptosis during autoimmune demyelination we investigated the effects of H2O2 and NO. in vitro on activated autoreactive CD4+ T cell lines capable of transferring experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). For detection and quantitation of apoptotic cells, DNA fragmentation was assessed by in situ tailing with fluorescein-ddUTP and subsequent flow cytometric analysis. H2O2 applied directly to the cell cultures for 6 to 18 hr at concentrations of 10 to 300 microM and ROI released by combination of hypoxanthine and xanthine oxidase (HX/XO) caused apoptosis in a dose-dependent manner in 13-33% of T cells of neuritogenic and encephalitogenic T cell lines. Apoptosis induction could be suppressed by the H2O2-neutralizing enzyme catalase. NO. released by the penicillamine derivative SNAP induced apoptosis to a similar extent as ROI. Maximum values were 38% in an encephalitogenic V beta 8.2-T cell receptor-bearing T cell line and 26% in a neuritogenic T cell line. T cell lines with specificity to ovalbumin revealed slightly lower susceptibility to apoptosis induction by all three kinds of trigger, which is, however, most probably not due to the different antigen specificity, but rather a result of fewer in vitro restimulation cycles of these cells. In neuritogenic cells high-dose (100 units/ml) exogenous interleukin-2 (IL-2) prevents H2O2-induced apoptosis. In conclusion, macrophage-derived reactive oxygen and nitrogen intermediates have the potency to limit inflammatory demyelination by elimination of autoreactive and bystander T cells via apoptotic cell death, and IL-2 is a rescue factor.
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PMID:Apoptosis of myelin-reactive T cells induced by reactive oxygen and nitrogen intermediates in vitro. 918 92

Inflammatory cells were obtained from the spinal cords of rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the expression of mRNA for interleukin-2 (IL-2), IL-4, IL-10 and interferon-gamma (IFN-gamma) by cells from groups of rats studied 10-21 days after inoculation. On all days of study, the inflammatory cells, which were predominantly lymphocytes, expressed mRNA for IL-2, IL-4, IL-10 and IFN-gamma. In the mRNA from normal rat spinal cord tissue, there was little expression of cytokine mRNA. Cells from a short-term MBP-reactive T cell line expressed all the cytokines. Densitometry was used to measure the products of PCR, to assess the expression of each cytokine relative to that of beta-actin. IL-2 mRNA was expressed throughout the course of disease and reached a peak on day 18, during late clinical recovery. IFN-gamma was expressed throughout the course of the disease and was also high during late recovery. IL-4 mRNA was present in the spinal cord throughout the course of the disease, with a slight rise during late recovery. Relative expression of IL-10 rose to a peak on days 17-19, during late recovery from clinical disease. This study indicates that IL-2, IL-4, IL-10 and IFN-gamma are expressed by inflammatory cells in the spinal cord in EAE, with the relative expression of all cytokines being high during late clinical recovery.
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PMID:Cytokine expression by inflammatory cells obtained from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein and adjuvants. 968 21

Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers T-cell activation, stimulation of the TCR alone may result in an anergic state or T-cell deletion, both possible mechanisms of tolerance induction. Here we show that T cells that are deficient in the adaptor molecule Cbl-b (ref. 3) do not require CD28 engagement for interleukin-2 production, and that the Cbl-b-null mutation (Cbl-b(-/-)) fully restores T-cell-dependent antibody responses in CD28-/- mice. The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells. In contrast, the activation of Vav, a guanine nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings indicate that Cbl-b may influence the CD28 dependence of T-cell activation by selectively suppressing TCR-mediated Vav activation. Mice deficient in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis.
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PMID:Cbl-b regulates the CD28 dependence of T-cell activation. 1064 9

Dysregulation of interleukin-2 (IL-2), the prototypical T cell growth factor and immunoregulatory cytokine, may modify self-tolerance and predisposition to autoimmunity. The available literature suggested that IL-2 could be hypothesized to either propagate or inhibit the development autoimmune demyelinating disorders of the central nervous system such as multiple sclerosis. Thus, the present study sought to test these competing hypotheses by examining whether disrupting one or both IL-2 gene alleles would render mice more or less vulnerable to experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein was used to induce EAE in C57BL/6-IL-2(-/-) knockout, C57BL/6-IL-2(+/-) heterozygote and C57BL/6-IL-2(+/+) wild-type mice. All of the wild-type and heterozygote mice developed signs of EAE compared with only 23% of the IL-2 knockout mice. Histopathological examination of lumbar spinal cord sections confirmed that subpial perivascular inflammatory infiltrates found in wild-type and heterozygote mice were absent in the unaffected IL-2 knockout mice. These data demonstrate that vulnerability to EAE is markedly reduced in C57BL/6 mice lacking IL-2, and suggest that this cytokine may play a critical role in autoimmune processes of the central nervous system.
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PMID:Interleukin-2 gene deletion produces a robust reduction in susceptibility to experimental autoimmune encephalomyelitis in C57BL/6 mice. 1078 9

Quinoline-3-carboxamide (Linomide) is a novel, synthetic immunomodulator acting via immunologic and non-immunologic mechanisms. It has shown efficacy against various malignancies, experimental autoimmune encephalomyelitis, and septic shock in animal models and has been investigated for clinical use in minimal residual myeloid leukemia with promising results. Interleukin-2 has shown considerable efficacy in palliative anti-tumor-treatment of advanced renal cell cancer, revealing remission rates of up to 40% in combination therapy regimens. Linomide is reported to exhibit synergistic effects with interleukin-2. Here we report on a clinical phase I/II study examining tolerance and efficacy of a combination therapy schedule of SQ interleukin-2 and PO Linomide in advanced renal cell cancer. Seventeen patients received 10 IU/m2 interleukin-2 per week for 8 weeks, resting interleukin-2 for another 8 weeks. In week 5 they started 5 mg Linomide daily, continued with 10 mg from week 7 to 16. No objective remissions were observed. Among 15 patients evaluable for response, 10 (66.7%) were progredient during the study. Three patients died during the observation period, including two not evaluable for response. Median survival was 4.0 months, median progression-free survival 2.5 months with a Kaplan-Meier estimate of 3.63 months. Fever, reduced general condition, nausea/vomiting, dyspnea, anorexia, chills and hypotension were the most common side effects, reaching WHO grade 3 in 6 and grade 4 in 2 cases. In summary, Linomide in combination with interleukin-2 provides no advantages in efficacy or toxicity over other therapy regimens employing interleukin-2.
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PMID:Linomide and interleukin-2 in patients with advanced renal cell carcinoma. 1085 12


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