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At least 19 recordsLinked to original sources
PubMed1996

Protection against experimental nervous system autoimmune diseases by a human immunodeficiency virus-1 Tat peptide-based polyvalent vaccine.

The human immunodeficiency virus-1 (HIV-1) Tat peptide is taken up by a variety of cells in vitro and in vivo (Anderson et al.: Biochem Biophys Res Commun 194:876-884, 1993; Fawell et al.: Proc Natl Acad Sci USA 91:664-668, 1994; Chen et al.: Anal Biochem 227:168-175, 1995). We have used Tat37-72, the fragment containing a domain binding to alpha v beta 5 integrin (Vogel et al.: J Cell Biol 121:461-468, 1993), to deliver a fusion protein of three pathogenic rat T-cell epitopes, MBP68-84, P2,53-78, and IRBP1169-1191 systemically and via mucoepithelial surfaces. This recombinant polyvalent vaccine peptide, toolbox101, is-depending on the route of administration-specifically immunosuppressive and can be used to vaccinate against experimental autoimmune encephalomyelitis, neuritis, and uveoretinitis and is, in addition, of therapeutic value.

AIDS Vaccines↗
PubMed1996

Suppression of experimental autoimmune neuritis by phosphodiesterase inhibitor pentoxifylline.

Phosphodiesterase inhibitor pentoxifylline (POX) has been shown to have multiple immunomodulatory effects in vitro and in vivo. It inhibits T cell proliferation, T helper 1-type cytokines, and tumor necrosis factor. We postulated that POX might have an in vivo immunomodulatory effect on a T-cell-mediated autoimmune peripheral nervous system disease, experimental autoimmune neuritis (EAN). We investigated the effect of POX on EAN in rats immunized with peripheral nerve myelin containing neuritogenic peptide SP26. At 200 mg/kg/day, there was significant suppression of clinical EAN, weight loss, and T cell proliferation to SP26 compared to controls. Proliferation of T cells from immunized rats to SP26 was suppressed by POX in vitro. These studies demonstrate a beneficial role for POX in EAN, with potential applicability to human autoimmune demyelination.

Animals↗
PubMed1990

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system was investigated. Administration of rat recombinant interferon-gamma markedly augmented both myelin-induced and T-cell line-mediated experimental autoimmune neuritis. Conversely, in vivo application of a monoclonal antibody to interferon-gamma suppressed the disease. Clinical and electrophysiological findings were corroborated by semiquantitative morphometric analysis. Mechanisms responsible for the enhancing effects of interferon-gamma include upregulation of major histocompatibility complex class II antigen expression in the nerve lesion, increased cellular influx of T cells and macrophages, and heightened macrophage activity with enhanced release of toxic oxygen species. These observations establish a pivotal role of the cytokine interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

Animals↗
PubMed1999

CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.

Amino Acid Sequence↗
PubMed2001

Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice.

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4(+), and CD8(+) T cells. Finally, CD4(+) T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2-deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have "cryptic" autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.

Aging↗
PubMed1994

Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat.

The influence of the immunosuppressive antibiotic agent 15-deoxyspergualin (DSG) on macrophages and autoreactive T helper lymphocytes from Lewis rats was analysed in vitro and in vivo. DSG did not inhibit antigen- or mitogen-induced proliferation of encephalitogenic or neuritogenic T helper cell lines in vitro. However, the presence of DSG during in vitro activation of the T cells strongly suppressed or completely abrogated their capacity to induce encephalitis (EAE) or neuritis (EAN) after adoptive transfer to naive rats, although expression of activation markers or adhesion molecules on the T line blasts was not down-regulated by DSG. Like activation-induced T cell proliferation, IL-2-dependent growth of CD4+ T line cells was not affected by DSG. Preincubation of CD4+ T line cells in DSG during IL-2-driven proliferation for 48 h, however, inhibited the subsequent antigen- but not mitogen-induced activation of these T cells, although neither density of T cell receptors nor other surface molecules involved in antigen recognition were lowered on the cells exposed to DSG. Similar to its effect in vitro, in vivo administration of DSG for 10 days even at a concentration with cumulative toxicity did not suppress in vitro proliferation of spleen cells induced by mitogen or a mitogenic combination of anti-CD2 antibodies. Furthermore, spleen cell and peripheral blood lymphocyte (PBL) surface antigens, particularly MHC molecules, were not altered by long-term treatment with DSG for 30 days. While there was a slight reduction in the number of polymorphonuclear cells in both populations, the proportion of the different leucocyte subpopulations remained unchanged. In contrast to the strong functional impact of DSG on autoreactive T helper cells, the drug did not inhibit the oxidative burst of macrophages or their MHC antigen expression. This study demonstrates a clear inhibitory effect of DSG on CD4+ T lymphocytes, but not macrophages. It provides an explanation for recent observations of a strong immunosuppressive in vivo effect of DSG on transplantation rejection and experimental autoimmune diseases, despite a normal mitogen response of T cells exposed to DSG in vivo and in vitro.

Animals↗
PubMed1997

DNA vaccines for the treatment of autoimmune disease.

DNA vaccines represent one of the most significant developments in vaccine technology in recent years. Although, in general, studies have primarily focused on the induction of protective immune responses against infectious pathogens, the technology may prove useful for other immune-related diseases, including autoimmunity. Autoimmune disease results from a breakdown in tolerance to self antigens; however, the same fundamental immunological reactions that control immune responses to foreign antigens are also likely to operate during the course of autoimmune disease. These include the reciprocal regulation of Th cell subsets. Th1 cells appear to be involved in many organ-specific autoimmune diseases while suppression of disease is associated with cells of the Th2 phenotype. It has been possible, therefore, to suppress many of the pathological consequences of autoimmunity by manipulating the Th1/Th2 cell balance. The induction of Th2 responses by DNA immunization might therefore be expected to have a profound effect on the course of autoimmune disease. Indeed, we have demonstrated that DNA immunization can protect animals against the autoimmune central nervous system inflammatory disease, experimental autoimmune encephalomyelitis (EAE). As many other autoantigens have now been identified, the application of this technology to other autoimmune diseases warrants investigation.

Animals↗
PubMed2004

Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment.

Peroxisomes are ubiquitous subcellular organelles and abnormality in their biogenesis and specific gene defects leads to fatal demyelinating disorders. We report that neuroinflammatory disease in brain of experimental autoimmune encephalomyelitis (EAE) rats decreased the peroxisomal functions. Degradation of very long chain fatty acids decreased by 47% and resulted in its accumulation (C26:0, 40%). Decreased activity (66% of control) of dihydroxyacetonephosphate acyltransferase (DHAP-AT), first enzyme in plasmalogens biosynthesis, resulted in decreased levels of plasmalogens (16-30%). Catalase activity, a peroxisomal enzyme, was also reduced (37%). Gene microarray analysis of EAE spinal cord showed significant decrease in transcripts encoding peroxisomal proteins including catalase (folds 3.2; p<0.001) and DHAP-AT (folds 2.6; p<0.001). These changes were confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, suggesting that decrease of peroxisomal functions in the central nervous system will have negative consequences for myelin integrity and repair because these lipids are major constituents of myelin. However, lovastatin (a cholesterol lowering and anti-inflammatory drug) administered during EAE induction provided protection against loss/down-regulation of peroxisomal functions. Attenuation of induction of neuroinflammatory mediators by statins in cultured brain cells [J. Clin. Invest. 100 (1997) 2671-2679], and in central nervous system of EAE animals and thus the EAE disease [J. Neurosci. Res. 66 (2001) 155-162] and the studies described here indicate that inflammatory mediators have a marked negative effect on peroxisomal functions and thus on myelin assembly and that these effects can be prevented by treatment with statins. These observations are of importance because statins are presently being tested as therapeutic agents against a number of neuroinflammatory demyelinating diseases.

ATP-Binding Cassette Transporters↗
PubMed2003

Infection with Mycobacterium bovis BCG diverts traffic of myelin oligodendroglial glycoprotein autoantigen-specific T cells away from the central nervous system and ameliorates experimental autoimmune encephalomyelitis.

Infectious agents have been proposed to influence susceptibility to autoimmune diseases such as multiple sclerosis. We induced a Th1-mediated central nervous system (CNS) autoimmune disease, experimental autoimmune encephalomyelitis (EAE) in mice with an ongoing infection with Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) to study this possibility. C57BL/6 mice infected with live BCG for 6 weeks were immunized with myelin oligodendroglial glycoprotein peptide (MOG(35-55)) to induce EAE. The clinical severity of EAE was reduced in BCG-infected mice in a BCG dose-dependent manner. Inflammatory-cell infiltration and demyelination of the spinal cord were significantly lessened in BCG-infected animals compared with uninfected EAE controls. ELISPOT and gamma interferon intracellular cytokine analysis of the frequency of antigen-specific CD4(+) T cells in the CNS and in BCG-induced granulomas and adoptive transfer of MOG(35-55)-specific green fluorescent protein-expressing cells into BCG-infected animals indicated that nervous tissue-specific (MOG(35-55)) CD4(+) T cells accumulate in the BCG-induced granuloma sites. These data suggest a novel mechanism for infection-mediated modulation of autoimmunity. We demonstrate that redirected trafficking of activated CNS antigen-specific CD4(+) T cells to local inflammatory sites induced by BCG infection modulates the initiation and progression of a Th1-mediated CNS autoimmune disease.

Adoptive Transfer↗
PubMed1988

Failure of amantadine hydrochloride to alter immune responses in the experimental allergic encephalomyelitis model of neuroautoimmune disease.

Amantadine hydrochloride has been reported efficacious in the symptomatic management of patients with multiple sclerosis (MS). To characterize further the potential effects of amantadine in MS, we studied the drug's effect on immunological parameters in the experimental allergic encephalomyelitis (EAE) model. Nine Lewis rats were used; 3 served as controls and 6 were EAE-induced. Three of the EAE-induced rats received amantadine (AMT) (0.3 g/kg/day) at the onset of EAE symptoms. Sera were collected post-AMT treatment and assayed for antimyelin basic protein antibody (anti-MBP) and 2'3'-cyclic nucleotide 3'-phosphohydrolase activity (CNP). The mean differences in the immunological parameters between treated and nontreated EAE-induced groups were not significant. These findings fail to demonstrate a specific effect of amantadine on immunologic responses tested in the EAE model, and do not support the notion that the effects of amantadine in MS are linked to basic alterations in immune responses.

Amantadine↗
PubMed1999

CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease.

Clinical signs of experimental autoimmune encephalomyelitis (EAE) are associated with the selective recruitment of CD4+ memory (CD45RBlow CD44high) T cells into the central nervous system (CNS). However, we have found that many of these recently recruited memory cells are CD44low, suggesting that the CD44 antigen may be involved in, and transiently lost during, the extravasation process. Indeed, administration of a CD44-specific antibody (IM7.8.1) induced leucocyte CD44 shedding and both prevented the development and ameliorated the severity of established EAE by inhibiting mononuclear cell infiltration into the CNS. Trafficking of cells into lymph nodes, however, a property mainly of naïve cells, was essentially unaffected. In contrast, treatment with antibody to very late activation antigen-4 (VLA-4) prevented homing to both the CNS and to lymph nodes. This study contests previous reports that dismissed a role for CD44 in inflammation of the CNS and, coupled with observations in murine dermatitis and arthritis, suggests that CD44 is involved in the homing of primed lymphocytes to sites of inflammation. CD44 should therefore be considered a target for immunotherapy of T-cell-mediated inflammatory diseases, such as multiple sclerosis.

Animals↗
PubMed1999

Immune regulation and CNS autoimmune disease.

The central nervous system is a demonstrated target of both clinical and experimental immune mediated disorders. Immune regulatory mechanisms operative at the levels of the systemic immune system, the blood brain barrier, and within the CNS parenchyma are important determinants of the intensity and duration of the tissue directed injury. Convergence of research, involving direct manipulation of specific cells and molecular mediators in animal models and in vitro analysis of human immune and neural cells and tissues, is providing increasing insight into the role of these immune regulatory functions and their potential to serve as therapeutic targets.

Animals↗
PubMed2003

New immunopathologic insights into multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in the pathogenesis of disease, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to a better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. We review the role of the immune system for the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies to identify the cause of MS.

Animals↗
PubMed2004

Adult gonadal hormones selectively regulate sexually dimorphic quantitative traits observed in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) are characterized by strong sexual dimorphisms, many of which may be due to genetically controlled sex hormone effects on the immune system, the central nervous system (CNS), or both. In the present study we used 487 gonadectomized and 376 intact age-matched F(2) mice generated through crosses of B10.S/SgMcdJ and SJL/J mice to assess the role of adult gonadal hormones in regulating clinical and histopathological quantitative traits (QT) associated with EAE in the context of genetic heterogeneity. We found that gonadectomy resulted in different effects, depending on the QT and the sex of the mouse. Ovariectomized mice on average had lower cumulative clinical disease scores, shorter duration of clinical signs, and increased peak disease scores. This trend was accompanied by a significant increase in the incidence of acute, progressive EAE which is more frequently seen in intact and orchiectomized males. Although spinal cord (SC) inflammation was the better predictor of clinical signs of EAE in both sexes, ovariectomized females had considerable reductions in nearly all histopathological QT in both the brain and SC. Orchiectomy resulted in modestly significant increases in disease severity and peak score and earlier onset of clinical signs. With the exception of SC demyelination and lesion scores, orchiectomy had no effect on histopathological QT. Importantly, gonadectomy reduced but did not completely abolish any of the sexually dimorphic clinical QT seen in intact mice. It did however, lead to a significant sexual dimorphism in incidence and severity not seen in intact mice. For histopathological QT, no sexual dimorphism was detected for brain lesions in either intact or gonadectomized mice. In contrast, SC histopathological QT exhibited significant sexual dimorphisms, which were impacted by gonadectomy. The results from this study indicate that within the context of genetic heterogeneity, circulating gonadal hormones influence both clinical and histopathological QT in this model of MS, but they do not solely account for the sexual dimorphisms seen in these traits. Thus, additional mechanisms must play a role in regulating gender differences in autoimmune disease of the CNS.

Animals↗
PubMed1990

Immunologic mechanisms in chronic demyelinating diseases of the central and peripheral nervous system.

MS and CIP are inflammatory diseases of the CNS and PNS that are characterized by focal demyelination. Both disorders are thought to involve autoimmune processes. The factors that lead to a chronic inflammatory process have not been completely defined, but the immune system is thought to play a prominent role as has been discussed in this chapter. The role of a persistent or recurrent viral exposure has not been reviewed here but may well be a contributing factor. Since chronic relapsing experimental encephalomyelitis in animal models is a T-cell-mediated disease that pathologically resembles MS, T cells are postulated to be of primary importance in human demyelinating diseases. Oligoclonal T-cell populations can be found in the CSF of MS patients, even though their antigenic specificity is not known. HLA associations (HLA Dw2 and HLA DR2 in MS and HLA Dw3 in chronic inflammatory neuropathy) might relate to the proposed immunopathogenesis, as class II antigens encoded by these loci might serve as restriction elements for T-cell recognition of an autoantigen by encephalitogenic cell populations. Humoral factors are thought to play an important role in the pathogenesis of CIP, as plasma exchange has been shown to be beneficial. Experimental work with an antimyelin glycoprotein monoclonal antibody demonstrates the in vivo demyelinating activity of antibodies as well as the importance of cellular elements in the demyelinating process. Finally, a number of immunoregulatory abnormalities have been demonstrated in MS patients that point to defects in immunoregulation, in particular in the generation of suppression. Decreases in AMLR in active MS might be of importance, as the AMLR is a reaction against self MHC determinants during which suppression is generated. Defects in suppression might allow self-reactive cells to escape regulation and cause inflammatory lesions in the nervous system.

Autoantibodies↗
PubMed2001

Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels.

Direct in vivo evidence is still lacking for alpha4-integrin-mediated T cell interaction with VCAM-1 on blood-brain barrier-endothelium in experimental autoimmune encephalomyelitis (EAE). To investigate a possible alpha4-integrin-mediated interaction of encephalitogenic T cell blasts with VCAM-1 on the blood-brain barrier white matter endothelium in vivo, we have developed a novel spinal cord window preparation that enabled us to directly visualize CNS white matter microcirculation by intravital fluorescence videomicroscopy. Our study provides the first in vivo evidence that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that alpha4-integrin mediates the G protein-independent capture and subsequently the G protein-dependent adhesion strengthening of T cell blasts to microvascular VCAM-1.

Animals↗