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)

Treatment of Lewis rats with a single dose of OX19 antibody, specific for rat CD5, uniformly prevented the development of experimental autoimmune encephalomyelitis (EAE). This protective effect had several notable characteristics: (1) it persisted for at least 10 days; (2) it could be achieved with either high doses of the antibody (> 200 micrograms) or lower doses (100-200 micrograms), which did not deplete T cell populations; and (3) the treated animals were able to mount comparable T cell responses to both myelin basic protein and myelin-unrelated antigens. In addition, antibody treatment consistently prevented the development of adoptively transferred EAE, suggesting that enhanced suppressor cell activity may have contributed to the protection. Antibodies such as OX19 appear capable of blocking the development of EAE, and perhaps other autoimmune diseases as well.
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PMID:Prevention of experimental autoimmune encephalomyelitis in Lewis rats by treatment with an anti-rat CD5 antibody (OX19). 128 May 33

Experimental allergic encephalomyelitis (EAE) was induced by adoptive transfer of myelin basic protein (MBP)-activated LEW spleen cells into (LEW x PVG/c) F1----LEW chimeras. By double-immunofluorescent staining using OX27, which is specific for RT1c, and monoclonal antibodies (mAb) against various T-cell antigens (TAg), inflammatory cells in the lesions of the central nervous system (CNS) were categorized into MBP-activated and transferred LEW T cells (TAg+ OX27-), accompanying T cells (TAg+ OX27+) of chimera origin and non-T cells (TAg- OX27+). Examination of the lesions at various stages of EAE revealed that transferred OX19 (CD5)+ T cells accounted for 46% of the total number of inflammatory cells at the preclinical stage, became reduced to 23% at the clinical stage and recovered to a level between those of the preclinical and clinical stages at the recovery stage. In parenchymal infiltrates, 93% of the total T cells were transferred cells at the preclinical stage, whereas 66% were present in perivascular aggregates. At the clinical stage, the proportion of transferred T cells in the parenchyma was not different from that in the perivascular cuffs. At the recovery stage, the proportion of transferred T cells in the parenchyma was increased. Collectively, MBP-activated and transferred T cells first appeared in the CNS parenchyma followed by infiltration of T and non-T cells of recipient (chimera) origin. All these inflammatory cells formed the lesions of full-blown EAE. At the recovery stage, inflammatory cells decreased in number in all the compartments of the CNS. Transferred T cells formed the major proportion of parenchymal infiltrates at this stage. These findings strongly suggest that transferred T cells remain in the CNS parenchyma longer than cells of chimera origin and that antigen-activated T cells have well-expressed CNS-homing activity.
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PMID:Adoptively transferred experimental allergic encephalomyelitis in chimeric rats: identification of transferred cells in the lesions of the central nervous system. 305 24

T cell vaccination, which protects rodents against experimental autoimmune encephalomyelitis (EAE), has been shown to induce anti-idiotypic response in the T cell compartment. CD5 B cells (B1 cells) are the main source of natural autoantibodies, and are often characterized by high idiotypic connectivity. In this study we examined the possibility that idiotypic connectivity in the B cell compartment may also play a role in the regulation of EAE. We inoculated CSJLF1 mice (H-2d,s) with a CD5 B cell line, the BCL1 lymphoma cells (H-2d), and subsequently induced EAE. The injection of as few as 1,000 BCL1 lymphoma cells significantly blocked the development of EAE. Injection of CD5-negative myeloma cells (SP2) had no effect on the pathogenesis of the disease. Unlike control animals, lymphocytes from BCL1 lymphoma-injected mice significantly proliferate in response to interleukin-5, a growth factor to CD5 B cells. The proliferative response of lymphocytes from BCL1 inoculated mice to mitogenic stimulation was rather unchanged, indicating that no general immunosuppression has been induced by inoculating BCLJ lymphoma. These experiments suggest that CD5 B cells may be involved in the regulation of EAE.
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PMID:Inoculation of BCL1 lymphoma cells into CSJL/J F1 mice inhibits acute experimental autoimmune encephalomyelitis. 751 Nov 33

In the steady state, interaction between T cells and antigen-presenting dendritic cells (DCs) leads to T cell tolerance. To examine the role of DC regulated peripheral tolerance in a model autoimmune disease, we delivered an encephalitogenic oligodendrocyte glycoprotein (MOG) peptide to DCs in vivo. We found that targeting MOG peptide to DCs resulted in a novel form of peripheral T cell tolerance that was sufficiently profound to prevent autoimmune experimental acute encephalomyelitis (EAE). The tolerized T cells were severely impaired in specific secondary responses to antigen in vivo but they were not intrinsically anergic since they remained highly responsive to T cell receptor (TCR) stimulation in vitro. The mechanism that mediates this dynamic antigen-specific T cell unresponsiveness differs from previously described forms of tolerance in that it requires that DCs induce CD5 expression on activated T cells.
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PMID:Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. 1518 35

The induction phase of experimental autoimmune encephalomyelitis (EAE) in mice is T cell dependent and coreceptors that regulate T cell activation modulate disease development. We report here that mice lacking CD5, an important modulator of T cell activation, exhibit significantly delayed onset and decreased severity of EAE. The resistance to EAE in CD5(-/-) mice was not due to the inability of T cells to respond efficiently to stimulation with MOG(35-55) but was associated with the presence of elevated frequency of apoptotic activated T cells in spleens and DLN. We also observed a net decrease in peripheral activated CD4(+) T cells in CD5(-/-) spleens and DLN 10 days after immunization. We further show that in vivo blockade of CD5 engagement after induction of EAE by soluble CD5-Fc, a treatment that induces elimination of activated T cells, promoted recovery from EAE. Our studies indicate that CD5 regulates survival of activated T cells and provides a target for treatment of T cell-dependent autoimmune diseases such as multiple sclerosis.
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PMID:Cutting edge: critical role for CD5 in experimental autoimmune encephalomyelitis: inhibition of engagement reverses disease in mice. 1532 50

The ability of autoreactive T cells to induce autoimmune pathology is dependent on their ability to respond to the level of autoantigen presented in the target organ. Emerging evidence suggests that at the population level, T cell sensitivity for self can be reduced by deletion of those cells bearing high-affinity T cell receptors (TCRs) or by sensory adaptation of individual cells. Here, we have investigated the mechanisms that prevent the induction of experimental autoimmune encephalomyelitis (EAE) when myelin basic protein (MBP)-reactive T cells are exposed to a strong, antigenic stimulus. Stimulation of MBP-reactive TCR transgenic T cells with a superagonist peptide led to extensive activation-induced cell death (AICD) through Fas signaling. Using T cells lacking Fas, we found that disruption of this deletional mechanism only partially increased EAE in response to superagonist, failing to restore susceptibility to the level found in response to the wild-type MBP peptide. A significant fraction of the MBP-reactive T cells was able to avoid AICD in response to superagonist, but these cells had a reduced sensitivity for an antigen that correlated with elevated levels of CD5. Therefore, when TCR affinity is fixed, autoreactive T cell sensitivity can be shifted to below a threshold for harm by a combination of AICD and sensory adaptation.
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PMID:Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation. 1581 4

SIT is a transmembrane adapter protein that modulates signals emanating from the T-cell receptor (TCR). Here, we have used gene-targeted mice to assess the role of SIT for T-cell development and peripheral T-cell functions. SIT(-/-) double-positive thymocytes show an upregulation of the activation markers CD5 and CD69, suggesting that SIT negatively regulates TCR-mediated signals at the CD4(+) CD8(+) stage of thymic development. This assumption is further supported by the observation that in female H-Y TCR transgenic mice, positive selection is enhanced and even converted to negative selection. Similarly, mature peripheral T cells are hyperresponsive towards TCR-mediated stimuli and produce larger amounts of T-helper 1 (TH1) cytokines, and SIT-deficient mice show an increased susceptibility to develop experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. These results demonstrate that SIT is a critical negative regulator of TCR-mediated signaling and finely tunes the signals required for thymic selection and peripheral T-cell activation.
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PMID:The transmembrane adapter protein SIT regulates thymic development and peripheral T-cell functions. 1610 3

Regulating the differentiation and persistence of encephalitogenic T cells is critical for the development of experimental autoimmune encephalomyelitis (EAE). We reported recently that CD5 has an engagement-dependent prosurvival activity in T cells that played a direct role in the induction and progression EAE. We predicted that CD5 regulates T cell apoptosis/survival through the activation of CK2, a prosurvival serine/threonine kinase that associates with the receptor. To test this hypothesis, we generated mice expressing CD5 with the inability to bind and activate CK2 and assessed their susceptibility to EAE. We found mice deficient in CD5-CK2 signaling pathway were mostly resistant to the development of EAE. Resistance to EAE was associated with a dramatic decrease in a population of effector infiltrating Th cells that coexpress IFN-gamma and IL-17 and, to a lesser extent, cells that express IFN-gamma or IL-17 in draining lymph nodes and spinal cords. We further show that T cells deficient in CD5-CK2 signaling hyperproliferate following primary stimulation; however, following restimulation, they rapidly develop nonresponsiveness and exhibit elevated activation-induced cell death. Our results provide a direct role for CD5-CK2 pathway in T cell activation and persistence of effector T cells in neuroinflammatory disease. This study predicts that targeting of IFN-gamma(+)/IL-17(+) infiltrating Th cells will be useful for the treatment of multiple sclerosis and other systemic autoimmune diseases.
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PMID:CD5-CK2 binding/activation-deficient mice are resistant to experimental autoimmune encephalomyelitis: protection is associated with diminished populations of IL-17-expressing T cells in the central nervous system. 1714 52

Central tolerance plays a significant role in preventing autoimmune diseases by eliminating T cells with high and intermediate avidity for self. To determine the manner of setting the threshold for deletion, we created a unique transgenic mouse strain with a diverse T cell population and globally increased TCR avidity for self-peptide/MHC complexes. Despite the adaptations aimed at reducing T cell reactivity (reduced TCR levels and increased levels of TCR signaling inhibitor CD5), transgenic mice displayed more severe experimental allergic encephalomyelitis and lupus. The numbers and activity of natural (CD4(+)CD25(+)) regulatory T cells were not altered. These findings demonstrate that the threshold for deletion is adaptable, allowing survival of T cells with higher avidity when TCR avidity is globally increased.
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PMID:Adaptable TCR avidity thresholds for negative selection. 1898 Oct 94

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1d(high)CD5(+) regulatory B cell subset (B10 cells) have been identified during the initiation and progression of EAE. Whether and how the regulatory functions of B10 cells and FoxP3(+) T regulatory cells (Tregs) overlap or influence EAE immunopathogenesis independently has remained unanswered. This study demonstrates that the number of endogenous or adoptively transferred B10 cells directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers expanded quickly within the spleen, but not CNS following myelin oligodendrocyte glycoprotein(35-55) immunization, which paralleled B10 cell regulation of disease initiation. The adoptive transfer of myelin oligodendrocyte glycoprotein(33-35)-sensitized B10 cells into wild-type mice reduced EAE initiation dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg numbers expanded significantly within the CNS during disease progression, which paralleled their negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells in vivo during disease initiation enhanced EAE pathogenesis, whereas Treg depletion enhanced late-phase disease. B10 cells did not regulate T cell proliferation during in vitro assays, but significantly altered CD4(+) T cell IFN-gamma and TNF-alpha production. Furthermore, B10 cells downregulated the ability of dendritic cells to act as APCs and thereby indirectly modulated T cell proliferation. Thus, B10 cells predominantly control disease initiation, whereas Tregs reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg functions shaping the normal course of EAE immunopathogenesis.
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PMID:Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. 2062 40


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