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)

The phenotype of T cells in the central nervous system (CNS) in two models of chronic inflammation (experimental allergic encephalomyelitis and Corynebacterium parvum-induced inflammation) was compared to that of T cells in gut and chronically inflamed subcutaneous tissue and lung. CNS T cells display a similar phenotype in both inflammatory models, and are phenotypically unique compared to T cells from the other inflamed tissues. T cells from inflamed CNS are mainly CD4+ and are the only population examined that express a typical activated/memory phenotype: CD44high/LFA-1high/ICAM-1high/CD45RBlow. The CNS T cells are alpha4beta7-integrin(negative), but express alpha4-integrin and activated beta1 integrin, suggesting expression of the alpha4beta1-heterodimer in an activated state. In contrast, most T cells in gut express low levels of activated beta1 integrin. The CNS T cells lack expression of alpha6 and alphaE integrin chains and L-selectin. In inflamed CNS and inflamed subcutaneous tissue, approximately 50% of T cells express high affinity ligands for P-selectin while fewer than 10% express high affinity ligands for E-selectin. In summary, our data show that, independent of the inflammatory stimulus, T cells recruited into the inflamed CNS are phenotypically distinct from T cells in other inflamed tissues. This finding leads us to hypothesize the existence of a phenotypically distinct 'CNS-seeking' T lymphocyte population.
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PMID:Adhesion molecule phenotype of T lymphocytes in inflamed CNS. 960 Jul 13

We have previously shown that following oral administration of myelin basic protein (MBP), regulatory T cells are generated from gut-associated lymphoid tissue and that these cells suppress experimental allergic encephalomyelitis (EAE). These regulatory T cells produce transforming growth factor-beta (TGF-beta) with various amounts of IL-4 and IL-10 and these TGF-beta-secreting T cells have been termed Th3 cells. T cells in lymphoid organs drained by mucosal sites secrete IL-4 as a primary T cell growth factor. In the present study, we examined the role of IL-4 on oral tolerance and in the generation of TGF-beta secreting cells. Treatment of (PLJ x SJL)F1 mice with intraperitoneal (i. p.) IL-4 and low-dose oral MBP (0.5 mg) given three times reduced the severity of EAE, whereas i.p. injection of IL-4 alone or oral MBP alone given in these suboptimal doses, showed no protection. Spleen cells from protected mice produced increased amounts of TGF-beta and reduced IFN-gamma upon stimulation with MBP in vitro. Mucosal MBP-specific IgA production was significantly increased in IL-4 plus MBP fed animals. Moreover, oral administration of IL-4 (1 microg per feeding) also enhanced the suppression of EAE by oral MBP and this protective effect was reversed by administration of anti-TGF-beta antibody in vivo. Reverse transcription-PCR showed enhanced suppression of IFN-gamma in Peyer's patch in animals fed MBP and IL-4 versus those fed MBP alone. We then investigated the role of IL-4 in the generation of TGF-beta-secreting cells using MBP Ac1-11 TCR transgenic animals. Cells were cultured with IL-2, IL-4, or IFN-gamma in the presence of MBP and limiting dilution analysis for cytokine-secreting cells performed. We found that IL-4, but not IL-2 or IFN-gamma, generated TGF-beta-secreting T cells from naive splenic T cells and that these cells provided help for IgA production. These findings demonstrate that IL-4 is a differentiation factor for TGF-beta-secreting Th3 cells and oral IL-4 has a synergistic effect on low-dose oral tolerance that is associated with increased TGF-beta secretion.
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PMID:IL-4 is a differentiation factor for transforming growth factor-beta secreting Th3 cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. 975 65

Injection of Brown-Norway rats with mercuric chloride (HgCl2) activates a T helper type 2 (Th2) autoimmune response, with production of a number of autoantibodies and vasculitis primarily affecting the gut. Glucocorticoids have been shown to suppress Th1 and to promote the development of Th2-type responses. Conversely dehydroepiandrosterone (DHEA) promotes Th1 responses with suppression of Th2 responses. This study set out to define the role of these hormones in this animal model. Rats were adrenalectomized (Adx) with no steroid replacement (n = 11), Adx with basal steroid replacement given by a 25 mg corticosterone pellet inserted subcutaneously (n = 13), or sham-Adx (n = 14) prior to administration of HgCl2. In both groups of Adx animals there was a delay in the production of immunoglobulin E (IgE) and serum concentrations on day 9 were marginally lower (P = 0.035, repeated measures ANOVA). All of the animals Adx with no steroid replacement and two Adx animals with steroid replacement died between 10 and 14 days after HgCl2 challenge. There was no difference in the severity of caecal vasculitis between the groups. A significant increase in adrenal size was noted following administration of HgCl2. Administration of subcutaneous DHEA implants (100 mg and 200 mg) had no significant effect on IgE concentrations or severity of vasculitis. These observations do not support the hypothesis that corticosterone and DHEA play a central role in setting the Th1/Th2 balance in this experimental Th2-mediated autoimmune disease; in contrast with the Th1-mediated autoimmune disease experimental allergic encephalomyelitis where corticosterone plays a key role in immunoregulation.
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PMID:The role of endogenous steroid hormones in the generation of T helper 2-mediated autoimmunity in mercuric chloride-treated Brown-Norway rats. 1065 52

A role for alpha4 integrins in different forms of the multiple sclerosis-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated, but the individual contributions of alpha4beta1, alpha4beta7, and the related alphaEbeta7 integrin have not been determined. The P7 integrins alpha4beta7 and alphaEbeta7 play a central role in chronic inflammation, mediating the trafficking, entry, and/or adhesion of lymphocytes in the inflamed pancreas and gut, and their ligands MAdCAM-1, VCAM-1 and E-cadherin are expressed on brain endothelial cells and/or on microvessels in the inflamed central nervous system. Here, we show that an antibody directed against the beta7 subunit greatly attenuates a non-remitting form of EAE, induced by adoptive transfer of myelin oligodendrocyte peptide (MOG35-55)-stimulated T cells. Combinational treatment with both anti-beta7 and alpha4 integrin subunit antibodies led to more rapid and complete remission than that obtained with anti-alpha4 antibody alone, potentially implicating a role for alphaEbeta7 in disease progression. Remission correlated with the down-regulation of the vascular addressins VCAM-1. MAdCAM-1, and ICAM-1 on cerebral blood vessels. Attenuated forms of disease were induced by adoptive transfer of either wild-type encephalitogenic T cells to beta7-deficient gene knockout mice, or of beta7-/-encephalitogenic T cells to wild-type recipients. The former finding indicates that beta7 + ve recruited cells contribute to disease progression. Thus alpha4beta1, alpha4beta7, and alphaEbeta7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis.
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PMID:Beta7 integrins contribute to demyelinating disease of the central nervous system. 1069 9

The concept of oral tolerance refers to a form of peripheral tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered nonfunctional or hyporesponsive by prior oral administration of an antigen. The primary mechanisms mediating oral tolerance include deletion, anergy of antigen-specific T cells and active cellular suppression, the primary determining factor being the dose of fed antigen. Low doses favor active suppression, whereas high doses favor deletion and anergy. Active cellular suppression is mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, which migrate to the systemic immune system. One of the primary mechanisms of active cellular suppression is via secretion of suppressive cytokines such as TGF-beta, IL-4, and IL-10 following antigen-specific triggering. TGF-beta is produced both by CD4+ and CD8+ GALT-derived T cells and is an important mediator of the active suppression component of oral tolerance. CD4+ cells that primarily produce TGF-beta appear to be a unique T-cell subset and termed Th3 cells. Oral tolerance was successfully studied in a variety of experimental models for autoimmune diseases, among them experimental autoimmune encephalomyelitis, experimental arthritis, experimental anti-phospholipid syndrome, experimental autoimmune uveoretinitis, experimental insulin dependent diabetes mellitus (IDDM), and experimental autoimmune myasthenia gravis. The results obtained in experimental animal models have led to the conduction of several clinical trials of oral tolerance in patients with multiple sclerosis, rheumatoid arthritis, uveitis, and IDDM. Conflicting results were obtained, and although some improvement has been noted in some of the patients, broad ranging clinical improvement has not yet been observed. A more accurate choice of antigens, as well as more precise dosing and timing of antigen-administration might lead to better results in the future.
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PMID:Immunomodulation of experimental autoimmune diseases via oral tolerance. 1077 Feb 68

Peripheral immune tolerance following i.v. administration of Ag has been shown to occur in the absence of B cells. Because different mechanisms have been identified for i.v. vs low dose oral tolerance and B cells are a predominant component of the gut-associated lymphoid tissue (GALT) they may play a role in tolerance induction following oral Ag. To examine the role of B cells in oral tolerance we fed low doses of OVA or myelin oligodendrocyte glycoprotein to B cell-deficient ( microMT) and wild-type C57BL/6 mice. Results showed that the GALT of naive wild-type and microMT mice was characterized by major differences in the cytokine microenvironment. Feeding low doses of 0.5 mg OVA or 250 microg myelin oligodendrocyte glycoprotein resulted in up-regulation of IL-4, IL-10, and TGF-beta in the GALT of wild-type but not microMT mice. Upon stimulation of popliteal node cells, in vitro induction of regulatory cytokines TGF-beta and IL-10 was observed in wild-type but not microMT mice. Greater protection against experimental autoimmune encephalomyelitis was found in wild-type mice. Oral tolerance in microMT and wild-type mice was found to proceed by different mechanisms. Anergy was observed from 0.5 mg to 250 ng in microMT mice but not in wild-type mice. Increased Ag was detected in the lymph of microMT mice. No cytokine-mediated suppression was found following lower doses from 100 ng to 500 pg in either group. These results demonstrate the importance of the B cell for the induction of cytokine-mediated suppression associated with low doses of Ag.
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PMID:B cell-deficient (mu MT) mice have alterations in the cytokine microenvironment of the gut-associated lymphoid tissue (GALT) and a defect in the low dose mechanism of oral tolerance. 1125 1

Th3 CD4+ regulatory cells were identified during the course of investigating mechanisms associated with oral tolerance. Different mechanisms of tolerance are induced following oral antigen administration, including active suppression, clonal anergy and deletion. Low doses favor active suppression whereas high doses favor anergy/deletion. Th3 regulatory cells form a unique T-cell subset which primarily secretes transforming growth factor (TGF)-beta, provides help for IgA and has suppressive properties for both Th1 and Th2 cells. Th3 type cells are distinct from the Th2 cells, as CD4+ TGF-beta-secreting cells with suppressive properties have been generated from interleukin (IL)-4-deficient animals. In vitro differentiation of Th3 cells from Th precursors from T-cell antigen receptor (TCR) transgenic mice is enhanced by culture with TGF-beta, IL-4, IL-10, and anti-IL-12. Th3 CD4+ myelin basic protein regulatory clones are structurally identical to Th1 encephalitogenic clones in TCR usage, MHC restriction and epitope recognition, but produce TGF-beta with various amounts of IL-4 and IL-10. Because Th3 regulatory cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. In vivo induction of Th3 cells and low dose oral tolerance is enhanced by oral administration of IL-4. Anti-CD86 but not anti-CD80 blocks the induction of Th3 cells associated with low dose oral tolerance. Th3 regulatory cells have been described in other systems (e.g. recovery from experimental allergic encephalomyelitis) but may be preferentially generated following oral antigen administration due to the gut immunologic milieu that is rich in TGF-beta and has a unique class of dendritic cells. CD4+CD25+ regulatory T-cell function also appears related to TGF-beta.
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PMID:Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. 1172 36

Experimental autoimmune encephalomyelitis (EAE) is mediated by CD4+ T cells which preferentially use the Vbeta8.2 TCR in response to myelin basic protein (MBP). Two strains of Tg mice (Valpha2.3/Vbeta8.2 and Valpha4/Vbeta8.2) have T cell receptors that recognize the NAc1-11 immunodominant epitope of MBP. We previously reported that oral administration of MBP protects both Valpha2.3/Vbeta8.2 and Valpha4/Vbeta8.2 mice from EAE; however, tolerance induction differs between strains and is dependent on the timing of oral antigen. Here we analyze the peripheral and gut-associated lymphoid tissue (GALT) environments of the two strains of Tg mice. Tg cells in the Peyer's patch (PP) but not the spleen of Valpha2.3/Vbeta8.2 mice demonstrate increased CD69 and decreased CD45RB relative to Valpha4/Vbeta8.2 mice. High levels of Th1 and Th2 cytokines, proliferative activity and CC chemokines (MCP-1) are observed in the periphery and GALT of Valpha2.3/Vbeta8.2 Tg mice. In contrast, more non-Tg CD4+ cells are seen in the PP of Valpha4/Vbeta8.2 mice. These studies suggest that activated Tg T cells and fewer potential regulatory cells in the PP of Valpha2.3/Vbeta8.2 Tg mice may influence oral tolerance.
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PMID:Differences between two strains of myelin basic protein (MBP) TCR transgenic mice: implications for tolerance induction. 1186 44

Oral tolerance (OT) consists of the oral administration of antigens (Ag) that could alter the response of the immune system. This is a form of peripheral immune tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered non functional or hyporesponsive by prior oral administration of Ag. It was first described in 1911 in animal models of anaphylaxis. This therapeutic approach requires the orally administration of Ag and the active participation of the gut-associated lymphoid tissue (GALT), a tissue comprising Peyer's patches, intraepitelial cells and villi containing epithelials cells which is a well organized immune network. The mechanisms by which OT is mediated included deletion or anergy and active cellular suppression. The primary factor determining which form of tolerance will be developed after oral administration of Ag is the Ag dosage. Thus, it is thought that low doses of Ag induce the generation of active suppression, via regulatory T cells in the GALT, which then migrate to the systemic immune system. These regulatory T cells produce down-regulatory cytokines such as IL4, IL10 and TGFbeta, a Th2 / Th3 cytokine pattern. Conversely, high dose of Ag favors anergy or clonal deletion. The phenomenon in which regulatory cells, as generated by oral tolerization, are primed in an Ag specific manner, but act in the respective microenvironment in a non-Ag specific manner is called bystander suppression. This phenomenon is of particular interest and explained the use of OT in T cell mediated autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type I diabetes, some diseases in which the autoAg remains unknown or where there are reactivities to multiple autoAgs. There were several studies demonstrating the effectiveness of orally administered Ag in different animal models of autoimmune diseases, such as experimental allergic encephalomyelitis, collagen induced arthritis, diabetes, but also uveitis, myastenia gravis and transplantation. These mouse or rat models of autoimmune diseases gave the rationale for the therapeutic use of OT in human and this therapeutic approach has been tried in MS and RA, using oral myelin or oral collagen, respectively. In RA, 4 trials of oral type II collagen (CII) in RA have been published. Taken together, these studies suggested that oral CII in RA gave a trend toward clinical improvement, with significance in only 2 studies. Bacterial extract from Escherichia coli containing heat shock proteins has been tried in oral treatment for RA. Two placebo controlled trials and 2 comparative studies gave favorable results for this bacterial extract with no or mild adverse events. Although oral/mucosal tolerance has given successful results in animal models of autoimmune diseases, the enthusiasm for this therapeutic approach in human diseases must be tempered. The discrepancies between the effectiveness of OT in animal models and the results in human trials raise some questions, the identification of the subgroup of patients who might respond to this treatment and the source (or nature) of the administered Ag (homologous versus heterologous), for instance.
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PMID:Oral tolerance in the treatment of rheumatoid arthritis. 1456 Dec 5

Oral tolerance is an immunomodulatory mechanism used by gut tissues to induce systemic tolerance to ingested proteins. In models of disease, such as experimental autoimmune encephalomyelitis, oral tolerance has been used to protect against paralysis induced by immunization with myelin proteins. Previous work in our laboratory has shown a role for the chemokine, CCL2, and its receptor in the induction of high dose oral tolerance. In the present study, we report that two CCR5 ligands, CCL4 and CCL5, are expressed in gut tissues after Ag feeding. CCR5(-/-) mice were unable to be tolerized by feeding a high dose of Ag and were not protected from developing experimental autoimmune encephalomyelitis. Moreover, CCR5(-/-) mice did not display cytokine deviation as normally seen after high dose oral Ag. Using a selective CCR5 antagonist, methionine-RANTES, CCL2 expression was inhibited, resulting in enhanced IL-12 production and the inability for mice treated with methionine-RANTES to become orally tolerized. This current study suggests that CCR5 ligands may function to modulate CCL2 levels in the gut after Ag feeding, promoting a cellular environment that favors tolerance rather than immunity.
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PMID:CCR5 regulates high dose oral tolerance by modulating CC chemokine ligand 2 levels in the GALT. 1521 Jul 89


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