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)

We have previously demonstrated that CD4+ suppressor T cells (Ts) inhibit the secretion of interferon (IFN)-gamma, but not interleukin (IL)-2, by effector cells of experimental autoimmune encephalomyelitis (EAE). Moreover, CD4+ Ts appear to regulate IFN-gamma by secretion of transforming growth factor-beta. We now show that CD4+ Ts produce a lymphokine with IL-4 activity in response to a determinant associated with EAE effector cells. CD4+ Ts do not proliferate or secrete IFN-gamma, IL-2, or IL-4 in response to myelin basic protein, nor do CD4+ Ts proliferate or secrete IL-2 when co-cultured with irradiated EAE effector cells. Rather, CD4+ Ts secrete IL-4 when co-cultured with either irradiated effector spleen cells or irradiated encephalitogenic line cells. CD4+ Ts do not secrete IL-4 in response to OVA-primed spleen cells, suggesting that the suppressor cells recognize a determinant specific to encephalitogenic T cells. Furthermore, CD4+ Ts secrete IL-4 when cultured with synthetic T cell receptor (TcR) V beta 8, but not TcR V beta 14 peptide, in the presence of antigen-presenting cells. This response is major histocompatibility complex class II restricted as demonstrated by inhibition of the response with anti-class II monoclonal antibody. These results suggest that CD4+ Ts recognize a determinant associated with TcR on the surface of EAE effector cells and respond by secreting IL-4, in a manner analogous to the Th2 lymphocyte subtype.
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PMID:CD4+ suppressor cells of autoimmune encephalomyelitis respond to T cell receptor-associated determinants on effector cells by interleukin-4 secretion. 137 16

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS). Administration of transforming growth factor-beta (TGF-beta) has been shown to inhibit EAE. In this study, the possible role of endogenous TGF-beta in the regulation of relapsing EAE produced by the transfer of myelin basic protein-specific T cell lines was assessed. Although TGF-beta is not present in the normal CNS, this cytokine was detected by immunohistology in areas of central nervous system inflammation in both acute and chronic disease. The administration of anti-TGF-beta at the disease onset led to a worsening of the clinical course of EAE and more extensive pathological lesions. These findings provide direct evidence for a role of endogenous TGF-beta in the remissions seen in chronic relapsing EAE.
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PMID:Evidence of endogenous regulatory function of transforming growth factor-beta 1 in experimental allergic encephalomyelitis. 137 98

Nylon wool adherent, CD4+ T cells from the spleens of rats that have recovered from experimental autoimmune encephalomyelitis (EAE) inhibit the in vitro production of IFN-gamma, but not IL-2, by effector cells of EAE when cocultured in the presence of myelin basic protein Ag. When anti-transforming growth factor-beta (TGF-beta) antibodies are added to the co-cultures, IFN-gamma production is restored to normal levels. Irrelevant control antibodies have no effect. The same pattern of response was obtained with cells incubated in serum-free medium. In other experiments, purified TGF-beta was added to cultures of effector cells in the presence of antigen. TGF-beta inhibited the production of IFN-gamma by these cells in a dose-dependent manner, but had no apparent inhibitory effect on IL-2 production. Finally, supernatants from cultures containing effector cells and CD4+ suppressor cells plus Ag contained measurable amounts of TGF-beta, whereas supernatants from cultures of effector cells plus Ag contained no measurable amounts of TGF-beta. These results suggest that CD4+ Ts cells of EAE regulate effector cells of EAE through a mechanism that involves the secretion of TGF-beta and that the inhibitory function of this cytokine can be reversed with neutralizing antibodies directed against TGF-beta.
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PMID:CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta. 167 2

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system. The effect of the immunosuppressive molecule transforming growth factor-beta, (TGF-beta 1) on chronic relapsing EAE produced by the transfer of myelin basic protein-specific T cell lines was studied. TGF-beta 1 markedly inhibited the activation and proliferation of myelin-basic protein-specific lymph node cells in vitro. This reduced the capacity of these cells to transfer EAE. In addition, administration of TGF-beta 1 in vivo consistently resulted in an improved clinical course, even when given during ongoing disease. Immunopathologic study demonstrated a marked reduction in central nervous system damage and expression of cell-surface lymphocyte function-associated Ag-1 and class II MHC molecules in TGF-beta 1-treated mice. These findings have identified TGF-beta 1 as a possible therapeutic agent for the human demyelinating disease multiple sclerosis.
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PMID:Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. 170 29

We previously reported that the CD4+ suppressor cells (Ts) that regulate recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) produce transforming growth factor-beta (TGF-beta). We also reported that TGF-beta downregulates interferon-gamma (IFN-gamma), but not interleukin-2 (IL-2) production, by the CD4+ effector T cells (Te) that mediate EAE. We now report that TGF-beta also inhibits the production of tumor necrosis factor/lymphotoxin (TNF/LT) by EAE effector cells. When activated in vitro with myelin basic protein (MBP), Te produced TNF/LT, as measured using a WEHI 164 cytotoxicity assay. The specificity of cytokine action was demonstrated using neutralizing antibodies to TNF/LT. When added to the Te+MBP cultures, TGF-beta inhibited TNF/LT production in a dose-dependent fashion. Moreover, neutralizing anti-TGF-beta antibodies augmented TNF/LT production in the Te+MBP cultures. We also confirm that TGF-beta inhibits adoptive transfer of EAE. In contrast, murine IL-10 only partially inhibited TNF/LT and IFN-gamma production by Te. We conclude that TGF-beta production by Ts plays a major role in recovery from EAE in the Lewis rat by inhibiting TNF/LT and IFN-gamma production by the effector cells that mediate EAE.
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PMID:Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis. 751 80

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
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PMID:Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. 752 Jun 5

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.
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PMID:Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. 752 60

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease in which peripheral lymphoid cells are activated by immunization with myelin proteins and become effector cells that traverse the central nervous system (CNS) capillaries and initiate inflammatory demyelinating lesions. The administration of transforming growth factor-beta (TGF-beta) has been shown previously to decrease the incidence and severity of EAE. In our studies we have determined: 1) the effects of TGF-beta injected at different intervals after the EAE-inducing immunization; 2) the effect of TGF-beta on the development of sensitized T cells, as assayed by the proliferative responses of T cells from lymph nodes and peripheral blood; 3) the extent of lymphoid cell infiltration in CNS of TGF-beta-treated and control mice; and 4) the role of endogenous TGF-beta and TNF in determining the severity of both acute and relapsing EAE. The onset of acute-EAE in SJL mice, induced by immunization with spinal cord homogenate in CFA and pertussigen, is on days 10 to 15. Although daily i.p. injections of 0.2 to 2 micrograms TGF-beta 1 or TGF-beta 2 on days 5 to 9 after immunization are highly protective, injections on days 1 to 5 or 9 to 13 are not. Moreover, anti-TGF-beta accelerates and aggrevates EAE when given on days 5 and 9, but not on day 12. Anti-TNF, injected on days 5 and 9, provides a comparable degree of protection as does TGF-beta. Similarly, in relapsing EAE, anti-TGF-beta increases, whereas anti-TNF decreases the incidence and severity of relapses. TGF-beta treatment on days 5 to 9 does not influence the appearance of sensitized cells in peripheral blood and lymph nodes, but does prevent the accumulation of T cells in brain and spinal cord, as assayed on days 15 to 20. It is concluded that the protective effect of TGF-beta is exerted at the level of the target organ, CNS and/or its vascular endothelium, rather than through a direct effect on lymphoid cells, and that there is a small window of 4 days in which TGF-beta exerts its protective effect.
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PMID:Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor. 833 93

In this study we have characterized apoptotic cell death of autoreactive T cells resulting from their interaction with astrocytes and the modulatory effect of steroid hormones. Time kinetics of T-cell activation by interferon (IFN)-gamma-treated astrocytes from neonatal Lewis rats and by professional antigen presenting cells (APCs) from bulk suspensions of thymus or spleen were performed. [3H]Thymidine incorporation of neuritogenic P2- and encephalitogenic myelin basic protein (MBP)-specific T-cell lines declined after 48 h in culture with astrocytes. A similar suppressive effect was observed when T cells were cocultured with thymic APCs and astrocytes. This effect disappeared when astrocytes were separated by a transwell system. After 72 h of culture with astrocytes a mean of 17.5 +/- 12.4% T cells exhibited morphological signs of apoptosis. Apoptosis was identified by light microscopy, and confirmed by electron microscopy, by in situ tailing reaction and by agarose gel electrophoresis. Glucocorticosteroids and oestrogen specifically enhanced T-cell apoptosis within 8 h (69.8 +/- 23.1% and 69 +/- 17.1%, respectively) when added after 72 h to the astrocyte system, but not at earlier time points of T-cell activation or when thymic APCs were used. Glucocorticoid-mediated T-cell apoptosis was inhibited by the steroid-receptor antagonist RU 486. Pregnenolone, lipocortin-1, indomethacin and transforming growth factor-beta did not induce apoptosis in this system. The steroid effect was not associated with CD28, IL-2 receptor, or transferrin-receptor expression, which were equally upregulated on T cells activated by astrocytes or thymic APC as shown by fluorescence activated cell sorting (FACS) analysis. We conclude that astrocytes as CNS-specific APC may render T cells susceptible for induction of apoptotic cell death. Some steroid hormones can markedly enhance this process in vitro and may augment an additional effect of a systemic corticosteroid response in vivo during recovery from autoimmune encephalomyelitis.
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PMID:Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo. 880 Sep 54

Experimental autoimmune encephalomyelitis (EAE) in rats is typically a brief and monophasic disease with sparse demyelination. However, inbred DA rats develop a demyelinating, prolonged and relapsing encephalomyelitis after immunization with rat spinal cord in incomplete Freund's adjuvant. This model enables studies of mechanisms related to chronicity and demyelination, two hallmarks of multiple sclerosis (MS). Here we have investigated, in situ, the dynamics of cytokine mRNA expression in the central nervous system (CNS) and peripheral lymphoid organs (lymph node cells and splenocytes) of diseased DA rats. We demonstrate that peripheral lymphoid cells stimulated in vitro with encephalitogenic peptides 69-87 and 87-101 of myelin basic protein responded with high mRNA expression for proinflammatory cytokines; interferon-gamma, interleukin-12 (IL-12), tumour necrosis factors alpha and beta, IL-1 beta and cytolysin. A high expression of mRNA for these proinflammatory cytokines was also observed in the CNS where it was accompanied by classical signs of inflammation such as expression of major histocompatibility complex class I and II, CD4, CD8 and IL-2 receptor. The expression of mRNA for proinflammatory cytokines was remarkably long-lasting in DA rats as compared to LEW rats which display a brief and monophasic EAE. Furthermore, mRNAs for putative immunodownmodulatory cytokines, i.e. transforming growth factor-beta (TGF-beta), IL-10 and IL-4 were almost absent in DA rats, in both the CNS and in vitro stimulated peripheral lymphoid cells, while their levels were elevated in the CNS of LEW rats during the recovery phase. We conclude that the MS-like prolonged and relapsing EAE in DA rats is associated with a prolonged production of proinflammatory cytokines and/or low or absent production of immunodownmodulatory cytokines.
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PMID:Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta. 882 81


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