Inhibition Of Experimental Allergic Encephalomyelitis Research Articles

PPARγ antagonists reverse the inhibition of neural antigen-specific Th 1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-Deoxy-Δ 12,14-Prostaglandin J 2

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARγ agonists on experimental allergic encephalomyelitis (EAE), a Th 1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARγ agonists, 15d-PGJ 2 and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th 1 differentiation and the PPARγ deficient heterozygous mice (PPARγ +/−) or those treated with PPARγ antagonists develop an exacerbated EAE in association with an augmented Th 1 response. In this study, we show that the PPARγ antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro- N-(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPARγ agonists, Ciglitazone and 15-Deoxy-Δ 12,14-Prostaglandin J 2, in C57BL/6 wild-type and PPARγ +/− mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNγ production and Th 1 differentiation inhibited by Ciglitazone and 15d-PGJ 2. These results suggest that Ciglitazone and 15d-PGJ 2 ameliorate EAE through PPARγ-dependent mechanisms and further confirm a physiological role for PPARγ in the regulation of CNS inflammation and demyelination in EAE.

The effect of Am-80, one of retinoids derivatives on experimental allergic encephalomyelitis in rats

Experimental allergic encephalomyelitis (EAE) is an autoimmune model with inflammation and demyelination in the central nervous system, which resembles the human demyelinating disorder, multiple sclerosis (MS). In this study, we investigated the effect of Am-80, a synthetic retinoid, on EAE in DA rats. DA rats immunized with complete Freund's adjuvant (CFA) supplemented with myelin basic protein (MBP) developed severe EAE which reached the peak 12 to 14 days after immunization. Am-80 and prednisolone administered orally for 12 days after immunization diminished the clinical symptoms and infiltration of inflammatory cells in a dose dependent manner. However, after stopping administration, EAE recurred in DA rats treated with Am-80, but not with prednisolone. The different responses between Am-80 and prednisolone were not due to the difference in the tolerability to the MBP because both inhibited the delayed-type hypersensitivity response to MBP only during administration. To investigate the mechanism how Am-80 alone delayed the response, the expressional levels of mRNA for interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in spinal cord were examined. Transcriptional levels of IL-6, IFN-γ and TNF-α were parallel with the clinical symptoms of the disease in Am-80-treated rats, that is, expressional levels of their mRNA were diminished during the administration of Am-80, which then increased as soon as the administration was stopped. Among them, the expression of IL-6 mRNA was more rapidly and highly relapsed than that of the other two cytokines mRNA. However, prednisolone attenuated transcriptions of all these cytokines throughout the experiment. Therefore, these findings suggested that the inhibition of EAE is, in part, related to the inhibition of IL-6 production. However, there are many possible mechanism in the suppression of EAE by Am-80, further experiments will be necessary.

Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel

Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is useful for preclinical testing for agents to be considered for treatment for this human demyelinating disease. Microtubules in lymphocytes play an important role in the cascade of human T cell activation, and paclitaxel (PTX), a microtubule stabilizer, can inhibit T cell function. A new formulation of micellar PTX, free of Cremophor ® and ethanol, was tested for its effect on the induction of EAE in Lewis rats. Adoptive EAE was induced with an encephalitogenic T cell line activated with guinea pig myelin basic protein (GP MBP) peptide 68–88. PTX (10 mg/kg) was administered 24 and 72 h after cell transfer. The clinical signs, fulminating in controls, were completely blocked by PTX, but mild CNS inflammation remained unaltered. A similar dose of PTX, given on days 6 and 8 to animals developing active EAE after immunization with GP MBP peptide 68–88 in complete Freund’s adjuvant, greatly reduced the severity of paralysis and delayed the onset of disease by 8–9 days. Marked weight loss and severe toxicity were noted with higher and more prolonged administration. In vitro micellar PTX inhibited activation of encephalitogenic T cells by both specific antigen and mitogen. Lower doses and longer treatment programs may provide effective treatment with acceptable adverse effects with this agent in the treatment of inflammatory demyelinating disease.

Inhibition of Experimental Allergic Encephalomyelitis with an Antibody that Recognizes a Novel Antigen Expressed on Lymphocytes, Endothelial Cells, and Microglia

Experimental allergic encephalomyelitis (EAE) is a frequently employed animal model of the human disease multiple sclerosis. EAE can be induced by adoptive transfer of CD4+ T cells that are specific for central nervous system (CNS) antigens, typically myelin proteins. Although the pathogenic mechanism or mechanisms responsible for the clinical signs and histological changes in EAE and multiple sclerosis are not fully defined, the entry of T lymphocytes and antigen recognition within the CNS are required. The present study describes the participation of a novel cell surface molecule with properties suggesting a role in cell-cell adhesion or co-stimulation, or both, in the development of EAE in the rat. The molecule is defined by the unique monoclonal antibody (mAb) TLD-4A2. The TLD-4A2 antigen is present on resting and activated T lymphocytes, activated CNS endothelial cells, and microglia. The antigen is normally distributed in many tissues including lymph node, thymus, and spleen, as well as in the inflamed CNS. Both its pattern of tissue distribution and immunoprecipitation and immunoblotting studies suggest that the TLD-4A2 antigen is a novel molecule. Treatment of rats with the purified 4A2 mAb resulted in the inhibition of the clinical signs of EAE and also decreased the number T cells and macrophages accumulating in the CNS parenchyma. TLD-4A2 antibody did not seem to directly interfere with T cell viability in vivo, as demonstrated by the ability to recover and stimulate CD4+ encephalitogenic T cells from cervical lymph nodes of 4A2-treated animals. In vitro, the antibody partially blocked T cell proliferation assays. These data suggest that the TLD-4A2 mAb recognizes a novel molecule expressed on lymphocytes, endothelial cells, and macrophages that may play a role in hematogenous cell traffic and the initiation of CNS inflammation.

IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice.

IL-10 and IL-4 were studied with respect to their capacity to inhibit experimental allergic encephalomyelitis (EAE) induced in SJL/J mice by immunization with the proteolipid protein peptide PLP139-151. Treatment with 2 micrograms IL-10/day from day 0 until day 12 delayed onset of disease and inhibited the severity of EAE. By contrast, a daily dose of 0.5 microgram IL-4 was ineffective. Instead of acting in a synergistic fashion, IL-4 even abrogated the inhibitory effect of IL-10. The effects of IL-10 and IL-4 treatment were largely consistent with the (lack of) ability of these cytokines to down-regulate the inflammatory response in brain tissue. Although IL-4 was ineffective in the inhibition of EAE, lymph node cells from IL-4-treated mice displayed a strongly inhibited peptide-specific IFN-gamma production. By contrast, IL-10, which was effective in inhibiting EAE, showed no significant inhibition of IFN-gamma at this level. Neither cytokine treatment resulted in detectable levels of peptide-specific IL-4. Indirect evidence for the activity of Th2 cells in vivo came from the observation that IL-10 inhibited the primary PLP139-151-specific IgG2a and IgG3 response in favor of IgG1, whereas IL-4 inhibited the primary antibody response to the peptide, regardless of subclass. The combination of IL-4 and IL-10 did not affect the subclass composition. The observation that IL-10-treated mice remained sensitive to re-induction of EAE is not in support of an important role of Th2 cells in regulating disease activity in this model of actively induced EAE.

Prior exposure to superantigen can inhibit or exacerbate autoimmune encephalomyelitis: T-cell repertoire engaged by the autoantigen determines clinical outcome

Experimental allergic encephalomyelitis (EAE) is inducible in experimental animals immunized with myelin basic protein (MBP), proteolipid protein (PLP) or their peptides. We compared T-cell responses to encephalitogenic epitopes of PLP(43–64) and MBP(Ac1–11) in a single mouse strain, (PL/J × SJL)F1. MBP(1–11)-specific T-cell hybridomas expressed predominantly TCR Vβ8 or Vβ4, while PLP(43–64)-specific hybridomas expressed a diverse TCR repertoire. To analyze the biologic significance of the TCR repertoire (limited vs. diverse) to disease susceptibility, we pretreated mice with a superantigen (SEB), and then induced disease with these autoantigens. Mice injected with SEB and immunized with MBP(Ac1–11) showed significant inhibition of EAE, whereas SEB-pretreated mice immunized with PLP(43–64) had an increased severity of EAE and developed a chronic disease. These data demonstrate that prior exposure to microbial superantigens can significantly alter the autoimmune disease course depending upon the TCR repertoire used by the autoantigen.

IL-10 PRODUCTION BY ADULT HUMAN DERIVED MICROGLIAL CELLS

Microglia, a population of central nervous system (CNS) macrophages, have been demonstrated to support immune accessory and effector functions in the CNS. Numerous studies support the role of microglia in CNS development and pathology, where activation of microglia is consistently noted. The current study investigated microglial immune functions under basal and activation conditions and assessed the ability of interleukin-10 (IL-10), added exogenously or produced by microglia, to down-regulate microglial functions. This report demonstrates that microglia from the adult human brain produce IL-10 following interferon-γ/lipopolysaccharide activation. Functionally, recombinant human IL-10 down-regulated basal HLA-DR expression by microglia and inhibited, in a dose-dependent response, the ability of microglia to stimulate CD4 + T-cells in antigen presentation assays. These data, together with recent observations of the inhibition of experimental allergic encephalomyelitis (EAE) following IL-10 administration and reduced CNS infection by Listeria monocytogenes after anti-IL-10 treatment, suggest that IL-10 production by microglia may have important immune-regulatory functions in CNS disease and disease models. Copyright © 1996 Elsevier Science Ltd.

Inhibition of experimental allergic encephalo-myelitis by means of perftoran administration

Inhibition of experimental allergic encephalo-myelitis by means of perftoran administration

Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone.

Peptide analogues of disease-associated epitopes were studied for inhibition of experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rats. EAE- and AA-associated analogues were selected as competitors because of their in vitro inhibitory activity on proliferation of encephalitogenic and arthritogenic T cells. Although the EAE-associated competitor had a superior major histocompatibility complex (MHC) binding affinity, the AA-associated competitor was a better inhibitor of the in vitro proliferation of arthritogenic T cells. Furthermore, although in vivo EAE was inhibited by both competitors, AA was only inhibited by the AA-associated competitor. Remarkably, in contrast to what was expected of a regular MHC competitor peptide, the AA-associated peptide analogue also prevented AA upon immunization before disease induction and appeared to induce T cell responses that crossreacted with the original disease-associated epitope. Therefore, it is concluded that antigen-specific regulatory mechanisms were involved in synergy with MHC competition. The integration of both qualities into a single "competitor-modulator" analogue peptide may lead to the development of novel, more effective, disease-specific immunomodulatory peptides.

Inhibition of experimental allergic encephalomyelitis by the α-glucosidase inhibitor castanospermine

The alkaloid castanospermine is a potent inhibitor of oligosaccharide processing in vitro. Our recent findings indicating the importance of carbohydrate moieties in some critical step of the neuro-immunologic inflammatory process of allergic encephalomyelitis prompted us to investigate the effect of castanospermine on this disease process. The alkaloid inhibited passively induced allergic encephalomyelitis in a dose-dependent manner when administered continuously for 7 days beginning at the time of lymphocyte transfer. Although clinical disease was totally inhibited, treated animals did have inflammatory lesions in the central nervous system. These lesions were qualitatively different from those seen in untreated animals in that the inflammatory cells were tightly packed around the vessels and showed little migration into surrounding tissues. Castanospermine also effectively inhibited clinical disease in recipient animals which had had a previous episode of allergic encephalomyelitis. Castanospermine did not alter the disease when treatment was started after the onset of clinical symptoms.

Suppression of experimental allergic encephalomyelitis in rats by mercuric chloride

Brown-Norway (BN) rats are uniquely susceptible to development of autoimmune phenomena and enlargement of lymph nodes and spleen after repeated injections of mercuric chloride. Despite its ability to produce autoimmunity, HgCl 2 inhibited the development in BN rats of experimental allergic encephalomyelitis (EAE), another autoimmune process. The inhibition by mercury was probably due to lack of the normal absorption and granulomatous reaction to the EAE inoculum in the enlarged lymph nodes draining the inoculation site. Lewis rats did not develop enlarged nodes from HgCl 2 treatment. Lewis lymph nodes absorbed the EAE inoculum abundantly and developed an extensive granulomatous reaction despite the mercury treatment, and there was only a slight inhibition of EAE. Therefore, the ability of HgCl 2 to produce lymphadenopathy in BN rats may be responsible for the inability of these rats to absorb the inoculated antigen. The mercury-induced failure of absorption was manifested as an inhibition of EAE in BN rats.

Inhibition of experimental allergic encephalomyelitis by a new anti-inflammatory compound--SK&F 86002.

Annals of the New York Academy of SciencesVolume 540, Issue 1 p. 578-580 Inhibition of Experimental Allergic Encephalomyelitis by a New Anti-Inflammatory Compound–SK&F 86002 M. J. DIMARTINO, M. J. DIMARTINO Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorC. E. WOLFF, C. E. WOLFF Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorG. K. CAMPBELL JR., G. K. CAMPBELL JR. Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorN. HANNA, N. HANNA Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this author M. J. DIMARTINO, M. J. DIMARTINO Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorC. E. WOLFF, C. E. WOLFF Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorG. K. CAMPBELL JR., G. K. CAMPBELL JR. Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this authorN. HANNA, N. HANNA Department of Immunology & Anti-infectives Therapy, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406–2799Search for more papers by this author First published: November 1988 https://doi.org/10.1111/j.1749-6632.1988.tb27179.xCitations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume540, Issue1Advances in NeuroimmunologyNovember 1988Pages 578-580 RelatedInformation

The mechanism of inhibition of experimental allergic encephalomyelitis in the rat by monoclonal antibody against CD4

Lewis rats with actively induced or passively transferred experimental allergic encephalomyelitis (EAE) were treated with a monoclonal antibody (MAb) which binds to the CD4 antigen of rat helper/inducer T cells. Actively immunized animals treated at the first onset of clinical signs experienced only a mild form of the disease and rapidly recovered while the majority of those treated prophylactically never showed clinical signs of EAE. Passively transferred EAE was also completely inhibited with anti-CD4 MAb. In treated animals which exhibited only mild clinical signs of EAE, spinal cord and cerebellar leukocyte infiltrates were quite similar to those in untreated rats but where anti-CD4 MAb treatment completely prevented clinical EAE, histological signs were minimal or absent. Like Lewis rats which have recovered naturally from EAE, those treated with anti-CD4 MAb were both resistant to a secondary challenge with myelin basic protein and harboured potential encephalitogenic cells which were capable of transferring disease to recipient rats. Disease in these recipients was, however, of much greater severity than that experienced by animals receiving cells from naturally recovered (untreated) donors. These data demonstrate that administration of anti-CD4 MAb to rats can prevent EAE by a mechanism which does not ablate the encephalitogenic CD4 + cells or prevent the development of resistance to EAE but which may inhibit the disease by preventing the function of already activated effector cells.

Suppression of experimental allergic encephalomyelitis by tilorone: cell transfer and interferon studies

Tilorone is known to induce interferon and to suppress experimental allergic encephalomyelitis (EAE) produced by active immunization. In the present work, tilorone was given to donors or recipients of the passive transfer form of EAE, using a localized variety of 1 or 4 days duration and a nonlocalized form of 8 days duration. The results indicated that tilorone inhibited EAE by retarding the clonal expansion in response to antigen, by a reversible inhibition of EAE effector cells, and probably by an effect on nonspecific reactive cells in the perivascular inflammatory infiltrates. Inhibition of EAE was not mediated by the induction of interferon, but was associated with depletion of T lymphocytes.

Inhibition of experimental allergic encephalomyelitis by carrier administered prior to challenge with encephalitogenic peptide-carrier conjugate.

Guinea pigs can be rendered unresponsive to experimental allergic encephalomyelitis (EAE) challenge by prior injections of myelin basic protein (BP) or peptides derived from BP. The synthesized tryptophan-containing peptide (TrpP, corresponding to residues 114-122) which is the primary encephalitogenic sequence in BP (for guinea pigs) had been conjugated to the non-central nervous system protein bovine serum albumin (BSA) and used for EAE challenge. It has been shown in this study that prechallenge treatment with the BSA carrier alone can significantly inhibit the induction of EAE by TrpP-BSA conjugate. That carrier treatment is immunologically specific was determined when prior treatment with cytochrome c did not protect animals from EAE challenge with TrpP conjugated to BSA. In addition, in disease induced with BP or TrpP, and while TrpP did protect guinea pigs challenged with TrpP, it did not protect those challenged with BP. This last finding raises the possibility of a second encephalitogenic sequence in BP or an important role for the carrier in the TrpP conjugate.

Cellular events in the induction of experimental allergic encephalomyelitis in rats.

Although both the T and B cells of the Lewis rat have immunoglobulin receptors for basic protein (BP) of myelin, and both cell types are required for antibody production to BP, the present results demonstrate that the T cells are the only cells required for the induction of experimental allergic encephalomyelitis (EAE). Both EAE and anti-BP were readily induced in thymectomized, irradiated Lewis rats reconstituted with normal thymus and bone marrow cells and challenged with BP in complete Freund's adjuvant. If the thymus cells were first treated with BP heavily labeled with 125I so as to eliminate (sucide) specific T cells, the recipients neither develop EAE nor produce antibody to BP. On the other hand, if the thymus cells were untreated and the specific B cells of bone marrow were eliminated by treatment with 125I-BP, EAE was not inhibited, although no antibody was produced. These results strongly suggest that the T cell is responsible for the induction of EAE although both the T and B cells are competent to respond to BP. Evidence was presented which suggests that neither suppressor T cells nor circulating antibody are involved in the inhibition of EAE by injection of Lewis rats with nonencephalitogenic preparations of BP. The immune status of T and B cells of the Lewis rat to BP was compared with the immune status of these cells in other species to thyroglobulin, where only the B cells appear to be competent. In this context, Brown Norway rats, which are resistant to the induction of EAE, also appear to lack T cells reactive to BP, although competent B cells are present.

Inhibition of experimental allergic encephalomyelitis in guinea pigs by administration of bacterial lipopolysaccharide.

Inhibition of experimental allergic encephalomyelitis in guinea pigs by administration of bacterial lipopolysaccharide.

Antigen-Induced Inhibition of Experimental Allergic Encephalomyelitis

Abstract Defined peptide fragments were isolated from the N-terminal half of the myelin basic protein (BP) molecule and employed for antigen-induced inhibition of experimental allergic encephalomyelitis (EAE). Guinea pigs pretreated with peptide 44–89, obtained by limited pepsin digestion and purified by column chromatography, were significantly protected against EAE subsequently induced by sensitization with BP in complete Freund's adjuvant. Peptide 1–20, derived by cyanogen bromide cleavage, did not inhibit EAE, nor did the synthetic EAE peptide (residues 114–122), although this peptide was only weakly encephalitogenic for guinea pigs. These findings directly support our previous conclusion that different sites on the BP molecule are responsible for induction and inhibition of EAE, and suggest that disease inhibition can be attributed, at least in part, to a site within peptide 44–89.

Inhibition of experimental allergic encephalomyelitis in rats severely depleted of T cells.

Lewis rats depleted of thymus-derived cells (B rats) failed to develop either experimental allergic encephalomyelitis or antibody against myelin basic protein. Lewis B rats reconstituted with 690 x 10(6) thymocytes developed experimental allergic encephalomyelitis and levels of antibody against myelin basic protein comparable to those of controls. The Lewis B rat model should be useful in the analysis of the role of thymus-derived cell populations and antibody in the induction of experimental allergic encephalomyelitis.

Antigen-Induced Inhibition of Experimental Allergic Encephalomyelitis

Abstract The smaller of the two rat myelin basic proteins (rat-S) was isolated by gel filtration and employed for antigen-induced inhibition of experimental allergic encephalomyelitis (EAE) in guinea pigs. Rat-S lacks a sequence of 40 amino acids which are present in the larger myelin basic protein including part of the major determinant which causes EAE in the guinea pig. The results show that non-encephalitogenic rat-S, given before sensitization with the large basic protein, significantly inhibits EAE in the guinea pig, although the protection provided by the large basic protein is somewhat more complete. These findings suggest that different sites on the basic protein molecule are responsible for the immunologic induction and inhibition, respectively, of EAE.