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Experimental autoimmune encephalomyelitis is an induced inflammatory and demyelinating disease of the central nervous system widely used as an animal model for multiple sclerosis. New insights into its pathophysiology have been possible due to recent immunological concepts. New therapeutical approaches have been designed and tested in experimental autoimmune encephalomyelitis and are now entering the clinical setting.
Experimental autoimmune encephalomyelitis (EAE) is an experimental demyelinating disease of rodents. In (PL/J x SJL) F1 mice, it is induced by immunization with the myelin basic protein peptide Ac1-11. Ac1-11 [4A], a myelin basic protein peptide analog with a single amino acid substitution, (i) binds to class II major histocompatibility complex molecules and stimulates encephalitogenic T cells in vitro better than Ac1-11, (ii) is nonimmunogenic and nonencephalitogenic in vivo in (PL/J x SJL)F1 mice, (iii) prevents EAE when administered before or at the time of immunization with Ac1-11, and (iv) prevents EAE when administered later, near the time of disease onset. Initial studies suggest that Ac1-11 [4A] does not prevent EAE by competitive inhibition or by activation of regulatory cells. Thus, substitution of a single amino acid in a myelin basic protein peptide confers the capacity to prevent rather than induce EAE, even after peptide-specific encephalitogenic T cells have been activated.
Experimental autoimmune encephalomyelitis (EAE) is an experimentally induced demyelinating disease mediated by CD4+ T cells specific for various myelin proteins including myelin basic protein (MBP) and myelin proteolipid protein (PLP). Although myelin- and other CNS-specific antibodies are produced in EAE, B cells and antibodies are thought by most not to play a decisive role in the induction of EAE. In this report we show that B cells serve as the major antigen-presenting cells (APC) during the T cell activation stage in lymph nodes, and that MBP-specific antibodies can greatly enhance the induction of EAE. The role of B cells as APC is demonstrated in B cell-depleted mice. EAE cannot be induced by antigen/complete Freund's adjuvant immunization unless these mice are locally reconstituted with B cells prior to immunization. The enhancing effect of antibodies is demonstrated in experiments in which EAE is induced by the adoptive transfer of encephalitogenic T cells. The adoptive transfer of large numbers of encephalitogenic T cells induces EAE in 90% of normal recipient mice, but only 33% of B cell-depleted mice get EAE at the same cell dose. The efficiency of EAE induction in B cell-depleted mice can be enhanced if MBP-specific antibodies are simultaneously administered. A similar enhancement is also seen in normal mice when the number of adoptively transferred T cells is limiting. We propose that MBP-specific antibodies enhance the presentation of myelin-derived antigens by APC in the CNS to the adoptively transferred encephalitogenic T cells.
Experimental autoimmune encephalomyelitis (EAE) is a mouse model that serves as an experimental tool for studying the etiology, pathogenesis, as well as new therapeutic approaches of multiple sclerosis (MS). EAE is a polygenic chronic inflammatory demyelinating disease of the nervous system that involves the interaction between genetic and environmental factors. Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis. However, progress in identifying new susceptibility genes outside the MHC locus has been slow. With the advent of new global methods for genetic analysis such as large-scale sequencing, gene expression profiling combined with classic linkage analysis and congenic and physical mapping progress is considerably accelerating. Here we review our preliminary work on the use of gene expression mapping to identify new putative genetic pathways contributing to the pathogenesis of EAE.
Experimental autoimmune encephalomyelitis is a disease of the central nervous system that can be readily induced in a variety of species by immunization with myelin proteins. It is one of the most commonly studied models of cell-mediated autoimmune disease and consequently has been important in the elucidation of many immunological functions in vivo. Nevertheless, very little is understood about the genetic and environmental factors that control the disease. Several groups have begun undertaking systematic genetic analyses in mice to identify loci that associate with increased susceptibility to disease. In this review, we will summarize the work that has been done to understand the genetic predisposition that makes certain inbred animals susceptible to disease and others resistant, and we will discuss some of the difficulties in the genetic analysis that have arisen due to the complexities of this disease model.
Experimental autoimmune encephalomyelitis (EAE) induction in TNF gene-targeted mice has resulted in conflicting reports in part due to the strong association of TNF with the MHC locus. To define the participation of TNF in EAE development, we back-crossed TNF-deficient mice (H-2b) into the SJL/J strain and directly compared them to H-2b congenic SJL or inbred SJL/J mice. Induction of EAE with myelin basic protein (MBP) revealed that H-2b congenic SJL mice are fully susceptible, indicating that the H-2b haplotype does not affect disease susceptibility. Using H-2b congenic SJL mice we show here that TNF deficiency modifies the normal course of EAE by considerably delaying the onset for approximately 5 days, suggesting that TNF is required for the normal initiation of MBP-induced EAE. However, TNF-deficient mice eventually developed severe EAE with perivascular inflammation and primary demyelination similar to wild-type controls, indicating that TNF is not essential during these processes. Taken together, these results indicate that although TNF is not required for the progression of MBP-induced EAE, it contributes positively by advancing the onset of disease.
Experimental autoimmune encephalomyelitis (EAE) has traditionally been thought to be almost exclusively mediated by CD4(+) effector T cells. Here, we provide evidence for the existence of mouse CD8(+) T cells that are specific for an epitope of the myelin oligodendrocyte glycoprotein (MOG). Using a panel of truncated MOG peptides, we have identified the minimal epitope recognized by these T cells as MOG 37-46. This peptide, while possessing relatively low affinity for H-2D(b), efficiently stimulates IFN-gamma production from MOG-specific CD8(+) T cell lines in vitro and induces EAE in vivo. To further characterize the magnitude and kinetics of expansion of the MOG-specific CD8(+) T cell population in vivo, we used MOG 37-50/H-2D(b) MHC tetramers to visualize MOG-specific CD8(+) effectors in the peripheral lymphoid organs and central nervous system during the course of EAE induction and progression. Our results identify MOG-specific CD8(+) T cells in the central nervous system prior to and after the onset of disease, suggesting that CD8(+) T cells are a possible target for therapeutic intervention during EAE.
Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell disease of the central nervous system (CNS) characterized by mononuclear cell infiltration, demyelination, and paralysis. Recent studies describing the relationship of chemokine expression with development of clinical disease have led to the hypothesis that distinct chemokine receptors corresponding to specific ligands are expressed by CNS-infiltrating antigen-specific encephalitogenic T cells as well as host-derived bystander T cells and monocytes. In an effort to study encephalitogenic T cell chemokine receptor expression, we examined CC chemokine receptor expression from resting, activated, and CNS-isolated CD4(+) T cells. CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, and CCR8 mRNA is expressed by normal CD4(+) T cells. In vitro activated T cells expressed CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, and CCR8 mRNA as well as CCR4. After EAE induction, CCR1 mRNA was expressed by donor-derived encephalitogenic and host-derived CD4(+) T cells isolated only from CNS and not from spleen. In vivo neutralization of the CCR1 ligand, macrophage inflammatory protein-1alpha (CCL3), resulted in less encephalitogenic CD4(+) T cell CNS infiltration. These results demonstrate the importance of CC chemokine receptor expression by CD4(+) encephalitogenic T cells for CNS infiltration and subsequent disease development.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory and neuroprotective proteins that are expressed during EAE and MS. We have shown recently that exogenous administration of Zn-MT-II to Lewis rats with EAE significantly reduced clinical symptoms and the inflammatory response, oxidative stress, and apoptosis of the infiltrated central nervous system areas. We show for the first time that Zn-MT-II treatment during EAE significantly prevents demyelination and axonal damage and transection, and stimulates oligodendroglial regeneration from precursor cells, as well as the expression of the growth factors basic fibroblast growth factor (bFGF), transforming growth factor (TGF)beta, neurotrophin-3 (NT-3), NT-4/5, and nerve growth factor (NGF). These beneficial effects of Zn-MT-II treatment could not be attributable to its zinc content per se. The present results support further the use of Zn-MT-II as a safe and successful therapy for multiple sclerosis.
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. Paralysis is "induced" by CD4+ T cells of the Th1 phenotype. Tumor necrosis factor (TNF), a Th1 type cytokine, has been shown to be upregulated in the CNS during the onset of EAE, and systemic manipulations of TNF have had substantial effects on disease progression. However, the precise role of TNF in EAE has been called into question by recent experiments utilizing TNF and lymphotoxin knockout mice. We demonstrate here that the local delivery of TNF by myelin basic protein (MBP)-specific T cells, retrovirally transduced to express TNF, exacerbated MBP-induced disease following adoptive transfer into syngeneic mice.
Experimental autoimmune encephalomyelitis (EAE) is an induced inflammatory and demyelinating disease of the central nervous system which shares many clinical and pathological features with and is considered the animal model of multiple sclerosis. There is extensive evidence that EAE is a Th1 disease eliciting secretion of proinflammatory cytokines like IFN-gamma or TNF-alpha, and it has been suggested that cytokine-induced oxidative stress could have a role in EAE neuropathology. However, the individual roles of these and other cytokines in the pathogenesis of the disease are still uncertain. Here we analyze the role of IFN-gamma during EAE by using both IFN-gamma receptor-knockout (IFN-gamma R(-/-)) and wild-type mice, both strains immunized with peptide 40-55 from rat myelin oligodendrocyte glycoprotein. The levels of oxidative stress were determined through the analysis of immunoreactivity for inducible NO synthase, nitrotyrosine, and malondialdehyde, as well as through the expression of the tissue-protective antioxidant factors metallothionein I+II (MT-I+II). We also examined the number of cells undergoing apoptosis as judged by using the TUNEL technique. The levels of oxidative stress, MT-I+II, and apoptotic cell death by EAE were significantly increased in all mice, though more so in IFN-gamma R(-/-) mice compared with wild-type mice. These data support the notion that IFN-gamma has a protective role against EAE.
Experimental autoimmune encephalomyelitis (EAE) is a model of T-cell mediated autoimmune disease. Active disease is mediated by myelin basic protein specific CD4+ T-cells, whose adoptive transfer can also induce passive disease. In the Lewis rat EAE is a transient disease inducing lasting resistance to rechallenge. The mechanisms of recovery and resistance are poorly understood. CD8+ suppressor T-cells have mostly been thought to be central, especially in resistance to reinduction of the disease. In this study we showed by complete depletion of CD8+ cells that this subset does not influence either recovery or resistance to EAE in the Lewis rat. This was further confirmed by depleting CD8+ cells only after recovery from acute EAE. Such depletion did not diminish the effective resistance to rechallenge. Recovery from and resistance to EAE appear not to require the presence of CD8+ cells.
Experimental autoimmune encephalomyelitis influenced catecholaminergic and indoleaminergic neurotransmitter systems in the central nervous system of Lewis rats. During paralysis, serotonin and noradrenaline were significantly reduced compared to animals injected with complete Freund's adjuvant in the posterior dorsomedial brainstem and in lower spinal cord segments. These diminutions remained after recovery from neurological signs in T11-S1. The serotonin metabolite 5-hydroxyindoleacetic acid was greatly augmented during the attack in all segments but was depleted during recovery in the lumbar spinal cord, which may indicate a normalized turnover at a reduced serotonin level. These results suggest functional impairment of monoaminergic neurons of the brainstem and spinal cord followed by permanent damage to some monoaminergic fibers in the spinal cord.
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) induced in rodents by activated CD4+ T cells specific for various myelin proteins such as myelin basic protein and proteolipid protein. The disease is characterized by breach of the blood-brain barrier, perivascular infiltration of leukocytes into the CNS, local inflammation and demyelination in the form of plaques. In this study, we evaluated the effect of administration of antibodies to two members of the beta 2 integrin sub-family of adhesion molecules, CD11a and CD11b, on the onset and progression of EAE. CD11a and CD11b are involved in cell-cell interactions leading to T cell and macrophage extravasation to inflammatory sites and T cell activation. Our results show that anti-CD11a antibodies could completely block the induction of EAE and anti-CD11b antibodies significantly delayed the onset and diminished the severity of clinical signs of EAE even when injections were initiated at the first appearance of clinical signs.
Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) is a chronic relapsing-remitting animal model of multiple sclerosis (MS). Neurofilament light (NF-L), a structural protein expressed in neuronal cells can be used to quantify the amount of neuronal damage in MS patients. An immunoassay was used to measure levels of neurofilament light in cerebrospinal fluid (CSF) in rats with myelin oligodendrocyte glycoprotein-induced EAE. Significantly increased levels of neurofilament were found in the immunized animals compared to the controls, strengthening the similarities in the diseases and the progression pattern between the animal model and MS. The turnover of NF-L during this disease is increased since significantly elevated levels also were identified in the spinal cord of the diseased animals and immunohistochemistry gave support for this observation. Monitoring neurofilament levels in EAE can be used to follow disease progression and effects of therapy.
Experimental autoimmune encephalomyelitis (EAE) is widely regarded as an animal model of the human disease multiple sclerosis. A multitude of studies has investigated the neuroantigen-specific T-cell mediated cytokine pattern present in animals with EAE. In particular, the role of the so-called Th1- and Th2-cytokines has been addressed. In a recent study, it has been demonstrated that IL-23 rather than IL-12 is critical for modulating the character of the developing immune response towards a proinflammatory response and leading to EAE. IL-17 is a crucial effector cytokine, whose production is specifically triggered by IL-23, and it has been shown to be an essential inflammatory mediator in other autoimmune diseases and inflammatory conditions. This led us to investigate the role of IL-17 in EAE. Strong antigen-specific production of IL-17 was demonstrated both in peripheral immune organs and in the CNS in acute and chronic EAE, as demonstrated by ELISPOT and RT-PCR analysis. Therapeutic neutralization of IL-17 with IL-17-receptor-Fc-protein in acute EAE ameliorated clinical symptoms. Neutralization of IL-17 with a monoclonal antibody also ameliorated the disease course. We conclude that IL-17 is crucially involved in the cytokine network as an effector cytokine in EAE.
Experimental autoimmune encephalomyelitis is the prototypic T cell-mediated autoimmune disease model. Classically, this disease was viewed in terms of type 1 versus type 2 immunity: the type 1 cytokines IFNgamma and TNFalpha promoting disease, whereas an IL-4-dominated, type 2 response was protective. However, studies in knockout mice do not support this paradigm. More recent data point to important roles for IL-23 and IL-17 (rather than IL-12 and IFNgamma) in the establishment and persistence of the inflammatory lesion. IL-10 appears to be the dominant cytokine mediating recovery. The source of IL-10 includes B cells (most probably in the peripheral lymphoid organs). However, the key IL-10-producing cell within the central nervous system is a CD4+CD25+ T cell population that has regulatory function and is critical to resolution of the disease.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS)-1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and tissue inhibitor of metalloproteinase (TIMP)-3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.