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PubMed2005

Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is a useful model for aiding the development of new treatments for MS. All therapies approved for MS ameliorate EAE. Two approved medications, glatiramer acetate and Natalizumab, were developed directly from studies in EAE. Several trials are ongoing in MS after success in EAE, including altered peptide ligands of myelin, DNA vaccines and statins. However, EAE has failed to predict the outcome of certain approaches. The reasons underlying such failures are discussed here.

Animals↗

PubMed2003

CD134 plays a crucial role in the pathogenesis of EAE and is upregulated in the CNS of patients with multiple sclerosis.

We investigated the role of the CD134 (also named OX40) molecule in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). We examined the susceptibility of Cd134(-/-) mice to EAE, an autoimmune murine model that is dependent on infiltrating CD4+ T lymphocytes reactive to myelin proteins. EAE induced by myelin oligodendrocyte glycoprotein (MOG) injection in Cd134(-/-) mice showed less severe clinical signs of disease and markedly reduced inflammatory infiltrates within the central nervous system (CNS). Resistance was associated with a strong reduction of pathogenic IFNgamma-producing T cells infiltrating the CNS of Cd134(-/-) mice. Furthermore, analysis of CNS tissue sections from EAE animals and MS patients revealed the presence of CD134+ cells that were localized in active lesions, mainly in perivascular infiltrates. The presence of CD134-expressing T cells in brain tissue of MS patients and EAE affected mice, together with the functional evidence provided by the significant decrease in disease score obtained in Cd134(-/-) mice, indicate that interfering with the CD134 molecule in T cells may be an appropriate target for therapeutic intervention in active MS.

Amino Acid Sequence↗

PubMed2006

MBP-PLP fusion protein-induced EAE in C57BL/6 mice.

Gene knock-out and knock-in mice are becoming increasingly indispensable for mechanism-oriented studies of EAE. Most gene-modified mice are on the C57BL/6 background, for which presently there are only two EAE models available, the MOG peptide 35-55 and the PLP 178-191 peptide induced disease. However, because MS is not a single pathogenic entity, different EAE models are required to reproduce and study its various features. Here we are introducing MBP-PLP fusion protein (MP4)-induced EAE for C57BL/6 mice. B cell- and CD8+ T cell-dependence, as well as multi-determinant recognition are among the unique features of this demyelinating EAE.

Animals↗

PubMed2005

Exploiting genotypic differences to identify genes important for EAE development.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease multiple sclerosis (MS) and is primarily driven by T helper type 1 (Th1) cells. Interleukin (IL)-12 and interferon (IFN)-gamma are important cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-gamma or IL-12 still develop EAE. We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-gamma -/- and IL-12 -/- animals to identify genes critical for development of EAE. Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in spleen during the disease. We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues. The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.

Animals↗

PubMed2004

[Ion channels and demyelination: basis of a treatment of experimental autoimmune encephalomyelitis (EAE) by potassium channel blockers].

Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound action potential decreased probably because conduction block occurred. Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by dendrotoxin-I or kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during demyelinating diseases. In a T-cell line reactive to myelin basic protein antigen, which is used to adoptively transfer experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response, cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type hypersensitivity response to myelin basic protein prevents and treats adoptive experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent immunosuppressive agents with beneficial symptomatic effects in experimental autoimmune encephalomyelitis.

Action Potentials↗

PubMed2001

Importance of cryptic myelin basic protein epitopes in the pathogenicity of acute and recurrent anterior uveitis associated with EAE.

Lewis rats immunized with myelin basic protein (MBP) develop experimental autoimmune encephalomyelitis (EAE) and associated anterior uveitis (AU), which can relapse without recurring of EAE. In this study, we analyzed the repertoire of MBP epitopes that play a role in acute and recurrent AU by injection of MBP synthetic peptides. In addition to the encephalitogenic epitopes 69-89 and 87-99, several cryptic epitopes were found to be strongly uveitogenic in Lewis rats upon immunization with synthetic peptides, including 100-120, 121-140 and 142-167. However, the peptide corresponding to the MBP residues 1-20 was uniquely capable of inducing AU without EAE. Immunization with intact MBP was not essential for the induction of the recurrence of AU. The responses of T cells from lymph nodes and spleens showed a dominant response to the original disease-induced epitope with responses to secondary epitopes. In conclusion, the analysis of pathogenic determinants important for the induction of uveitis provides further evidence that MBP-specific T cells also contribute to the pathogenesis of anterior uveitis. Moreover, this also suggests that a distinct immunoregulatory mechanism exists in the eye and spinal cord because of the uniqueness of the epitope 1-20 in AU but not EAE, and the capability of MBP-specific T cells of inducing AU without EAE.

Acute Disease↗

PubMed1996

Epitope spreading occurs in active but not passive EAE induced by myelin basic protein.

Using experimental allergic encephalomyelitis, EAE, as a model for the study of autoimmune demyelinating disease in the CNS, previous studies have indicated that spread may occur with respect to the specificity of T cell responses during disease. This phenomenon, known as epitope spreading, is central to therapeutic strategies in multiple sclerosis (MS). However, in EAE, the clinical course, neuropathology and immunopathogenesis vary depending upon host factors and the method of disease induction. Since passive EAE in SJL/J mice resembles MS clinically and neuropathologically, this model was chosen to study the immune phenomenon of epitope spreading. T cells specific for whole 18.5 kDa MBP were used to initiate disease since MBP or one of its naturally occurring cleavage fragments may initiate a more physiological immune response than one generated to an artificially designed synthetic peptide. While a progressive increase in T cell responsiveness specific for the immunodominant MBP 87-106 region was observed during disease, there was no evidence of either intermolecular epitope spreading to the immunodominant region of proteolipid protein (PLP) 139-151 or of intramolecular epitope spreading to the exon 2 encoded region of MBP, which is spliced out of 18.5 kDa MBP. In addition there was no shift in immunodominance toward the subdominant MBP 16-35 region during disease. In contrast during active EAE induced by MBP, epitope spreading to the immunodominant epitope of PLP, 139-151, was observed. These data demonstrate that immune responses generated during passive versus active EAE may differ, and suggest that significant epitope spreading does not occur in chronic relapsing demyelinating disease initiated with T cells specific for whole MBP in the absence of exogenous antigen, complete Freund's adjuvant and pertussis. Implications of these findings with regard to epitope spreading in MS are discussed.

Adoptive Transfer↗

PubMed1997

Protection from experimental autoimmune encephalomyelitis (EAE): non-depleting anti-CD4 mAb treatment induces peripheral T-cell tolerance to MBP in PL/J mice.

Following pre-treatment with a non-depleting anti-CD4 mAb (H129.19) that produces long-lasting receptor saturation, PL/J mice were fully protected from experimental auto-immune encephalomyelitis (EAE) induced by injection of myelin basic protein (MBP). These mice did not develop EAE following MBP re-challenge 5-10 weeks later when the CD4+ cells were no longer coated by the mAb and their lymph node cells were specifically unresponsive to MBP stimulation in vitro. Moreover, superantigen staphylococcal enterotoxin B (SEB) inoculation, which re-induces EAE in MBP immunized mice, failed to activate encephalitogenic T-cells in anti-CD4 + MBP treated mice, even after MBP re-challenge, indicating that tolerance in the peripheral T-cell compartment was achieved. However, MBP re-challenge 16 weeks later, but not SEB, produced an acute episode of EAE in these mice, while it failed to induce disease in a parallel group of adult thymectomized mice. These results indicate that no memory of the first priming exists at this time and that new MBP-specific T-cell precursors are peripheralized and produce EAE after MBP recognition.

Animals↗

PubMed1998

Interleukin-1 receptor antagonist suppresses experimental autoimmune encephalomyelitis (EAE) in rats by influencing the activation and proliferation of encephalitogenic cells.

Considering the role of pleiotropic interleukin-1 (IL-1) in inflammation and autoimmunity, studies were designed to examine whether specific blockade of IL-1 may influence these processes in the CNS. Although the role of CD4+ T cells in eliciting clinical signs of experimental autoimmune encephalomyelitis (EAE) has been unequivocally demonstrated, the exact mechanism by which encephalitogenic cells initiate disease process and bring about clinical signs still remains to be defined. We have evaluated the effect of human recombinant interleukin-1 receptor antagonist (IL-1Ra) in vivo on the course of actively induced EAE in highly susceptible Dark Agouti (DA) rats. The rats which were treated during the induction phase of disease (days 0-6) with IL-1Ra (350 microg/rat/day) developed milder signs of EAE, when compared to saline-treated control animals immunized with encephalitogen, which developed severe single episode disease. The transfer of lymph node cells (LNC) isolated from MBP-primed DA rats and stimulated in vitro with MBP and ConA to naive syngeneic animals resulted in the development of EAE in all recipients. However, rats injected with LNC that have been stimulated in vitro in the presence of IL-1Ra (10 microg/ml) developed significantly milder disease. Diminished encephalitogenic capacity of LNC correlated with lower proliferative response to antigen and mitogen and decreased expression of IL-2 receptors. These data provide further evidence that IL-1 is an important factor for activation of EAE inducing T lymphocytes.

Animals↗

PubMed1998

Nitric oxide is a potential down-regulating molecule in autoimmune disease: inhibition of nitric oxide production renders PVG rats highly susceptible to EAE.

Rat strains vary in their susceptibility to experimental autoimmune encephalomyelitis (EAE) and in many cases, factors other than MHC antigens are thought to play a role in this. We found that PVG rats, which have a very low susceptibility to EAE, were rendered highly susceptible to clinical disease when treated with N-methylarginine (NMA) an inhibitor of nitric oxide synthase (NOS). The clinical course of the ensuing disease in NMA-treated PVG rats was in most cases fulminating in nature and accompanied by some mortality. Following immunisation with myelin basic protein (MBP)-complete Freund's adjuvant (CFA), PVG rats developed higher serum levels of the surrogate markers of nitric oxide production, reactive nitrogen intermediates (RNI; nitrite and nitrate), than did their Lewis counterparts. This in vivo finding was reflected in vitro, where the levels of RNI produced in 24, 48 and 72 h IFN-gamma-stimulated spleen cell cultures for PVG rats were significantly higher than those for Lewis rats. A mechanism by which increased NO production might protect PVG rats against clinical EAE was suggested by the finding that lymph node cells, isolated from NMA-treated MBP-immunised PVG rats, proliferated in response to MBP at a rate approximately 3 x greater than those from MBP-immunised, saline treated rats. Thus, the greater number of MBP-specific T cells generated in the NOS inhibitor-treated vs. untreated rats could account for their increased susceptibility to developing clinical EAE. The findings in this study suggest that NO plays a role in protecting PVG rats against developing EAE.

Animals↗

PubMed1999

CTLA-4-Fc treatment of ongoing EAE improves recovery, but has no effect upon relapse rate. Implications for the mechanisms involved in disease perpetuation.

Several laboratories including ours have shown that T cell co-stimulation mediated through B7-1 or B7-2 is critical to the initiation of EAE. The role of T cell co-stimulation in ongoing EAE is less clear. In the present study, 32 mice with established EAE were randomly assigned to receive treatment with either CTLA-4-Fc or control Ig. Mice were followed daily by clinical scoring for 2 months post-immunization. A significant improvement in the degree of recovery following the acute episode and following relapses of EAE was observed in those mice randomized to CTLA-4-Fc treatment. Full clinical remission occurred twice as often in the CTLA-4-Fc group as in those mice receiving placebo, whereas placebo-treated mice were more likely to develop a stable prolonged neurologic deficit. Serial clinical scoring revealed no effect of CTLA-4-Fc upon relapse rate, with greater than 80% of the mice in each group displaying at least one clinical EAE relapse. In that the activation of memory T cells is relatively independent of T cell co-stimulation, these results indicate that development of chronic disease is associated with the activation of naive T cells and the recruitment of the latter cells into the disease process. Blocking B7 molecules may be beneficial in the treatment of established CNS inflammatory demyelinating diseases such as multiple sclerosis.

Abatacept↗

PubMed1999

Characterization of eae+ Escherichia coli isolated from healthy and diarrheic calves.

Strains of Escherichia coli from 101 healthy and 114 diarrheic calves were screened by PCR for the eae (intimin) gene and Shiga toxin genes (stx). Each eae+ and eae/stx+ strain was examined for antimicrobial susceptibility, enterohemolysin activity, and the somatic O antigen was determined. An immunoassay was used to detect Shiga toxin antigens for the eae/stx+ E. coli. Significantly more (p = 0.005) of the healthy calves carried eae+ and eae/stx+ E. coli in their feces when compared to strains from diarrheic calves. Moreover, Shiga toxin antigens were detected significantly more (p = 0.001) often among the eae/stx+ strains from healthy calves when compared to eae/stx+ strains from diarrheic calves. However, significantly more (p = 0.001) of the eae+ and eae/stx+ strains from diarrheic calves were resistant to at least one of the antimicrobials tested, and the strains from diarrheic calves had a significantly (p = 0.05) higher rate of antimicrobial resistance to at least two different antimicrobial classes. No significant difference (p> or =0.05) was detected among the eae+ and eae/stx+ strains from healthy and diarrheic calves for enterohemolysin production. Serogroups O-negative, O5, O26, and O111 were predominate among both healthy and diarrheic calves.

Adhesins, Bacterial↗

PubMed1996

Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE).

T cell receptor (TCR)-recognizing regulatory cells, induced after vaccination with self-reactive T cells or TCR peptides, have been shown to prevent autoimmunity. We have asked whether this regulation is involved in the maintenance of peripheral tolerance to myelin basic protein (MBP) in an autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). Antigen-induced EAE in (SJL x B10.PL)F1 mice is transient in that most animals recover permanently from the disease. Most of the initial encephalitogenic T cells recognize MBP Ac1-9 and predominantly use the TCR V beta 8.2 gene segment. In mice recovering from MBP-induced EAE, regulatory CD4+ T cells (Treg) specific for a single immunodominant TCR peptide B5 (76-101) from framework region 3 of the V beta 8.2 chain, become primed. We have earlier shown that cloned B5-reactive Treg can specifically downregulate responses to Ac1-9 and also protect mice from EAE. These CD4 Treg clones predominantly use the TCR V beta 14 or V beta 3 gene segments. Here we have directly tested whether deletion/blocking of the Treg from the peripheral repertoire affects the spontaneous recovery from EAE. Treatment of F1 mice with appropriate V beta-specific monoclonal antibodies resulted in an increase in the severity and duration of the disease; even relapses were seen in one-third to one-half of the Treg-deleted mice. Interestingly, chronic disease in treated mice appears to be due to the presence of Ac1-9-specific T cells. Thus, once self-tolerance to MBP is broken by immunization with the antigen in strong adjuvant, TCR peptide-specific CD4 Treg cells participate in reestablishing peripheral tolerance. Thus, a failure to generate Treg may be implicated in chronic autoimmune conditions.

Adoptive Transfer↗

PubMed1992

Distribution of the blood-brain barrier in heterotopic brain transplants and its relationship to the lesions of EAE.

The blood-brain barrier (BBB) is recognized as a barrier to the trafficking of molecules and cellular elements into the central nervous system (CNS). Horseradish peroxidase (HRP) exclusion is used as a measure of BBB integrity. The BBB is altered and becomes permeable during the course of experimental allergic encephalomyelitis (EAE). Heterotopic brain transplantation into the anterior eye chamber is a technique for studying genetic influences and the role of individual cell types on the development of EAE. Prior to EAE induction, HRP is excluded from the central portion of the transplant, demonstrating an intact BBB. In contrast, HRP localization is found at the periphery of the transplant, suggesting an incomplete barrier. However, EAE lesions typically occur within the more central regions of the transplant, where the BBB is intact, and not at peripherally located "leaky" areas. This suggests that endothelial cells at intact BBB sites may direct trafficking of lymphocytes (gating) into the CNS during the development of EAE, rather than the passive entry of lymphocytes into the CNS through a leaky BBB.

Animals↗

PubMed1998

Apoptotic cells are present in the CNS throughout acute and chronic-progressive EAE in the absence of clinical recovery.

Experimental allergic encephalomyelitis (EAE) is an autoimmune, demyelinating disorder of the central nervous system induced in susceptible animals as a model for the human disease multiple sclerosis. Antibodies against the leukocyte adhesion molecule alpha4 integrin have been shown to prevent and reverse acute and chronic EAE of the guinea pig. The results presented in this paper implicate apoptosis as the mechanism of reversal of EAE following treatment with anti-alpha4 integrin antibody. Apoptotic cells were observed in the central nervous system (CNS) throughout chronic-progressive EAE of the guinea pig in the absence of clinical recovery. Many of the apoptotic cells were identified as T cells using immunohistochemistry. Similarly, apoptotic cells were present in the CNS of animals during anti-alpha4 integrin-mediated recovery from acute and chronic disease. Therefore, anti-alpha4 integrin-mediated recovery from EAE is due to the prevention of the influx of new inflammatory cells into the CNS that are required to replace those undergoing apoptosis.

Acute Disease↗

PubMed2006

Allelic subtyping of the intimin locus (eae) of pathogenic Escherichia coli by fluorescent RFLP.

Intimin is a highly polymorphic protein encoded by the eae gene and plays a crucial role in the attaching-effacing phenotype of diarrheagenic Escherichia coli and related pathogens. We have developed a method to quickly and accurately uncover allelic variation at the eae locus through the use of fluorescent RFLP (fRFLP). Application of fRFLP to 151 eae-positive strains (including the newly described Escherichia albertii) revealed 26 different fRFLP types that correspond to 20 of the 28 previously described eae alleles. Two sequence variants of the gamma, iota, kappa, and zeta alleles and three variants of epsilon were also observed. In addition to being reliable and accurate, the method can be easily adapted to accommodate new eae allelic sequences, as they become known.

Adhesins, Bacterial↗

PubMed1991

Specific immunoregulation of the induction and effector stages of relapsing EAE via neuroantigen-specific tolerance induction.

The effects of neuroantigen-specific tolerance on the induction and effector stages of relapsing experimental autoimmune encephalomyelitis (R-EAE) were examined. The incidence of clinical and histologic signs of active MSCH-induced R-EAE, and accompanying neuroantigen-specific DTH responses, were dramatically reduced in SJL/J mice tolerized via the i.v. injection of syngeneic splenocytes coupled with MSCH, PLP, or encephalitogenic PLP peptides 7-14 days before priming. MBP-specific tolerance was not effective in preventing active R-EAE. In contrast to MSCH-induced active R-EAE, treatment of recipient mice with splenocytes coupled with MBP and the encephalitogenic MBP 84-104 peptide, but not with PLP, suppressed of clinical signs of adoptive R-EAE mediated by MBP-specific effector T cells in a dose-dependent manner. Neuroantigen-coupled splenocytes were also efficient in treating established disease as tolerization of SJL/J mice after the first incidence of clinical disease significantly reduced the incidence and severity of subsequent paralytic relapses. Antigen-specific tolerance thus provides a powerful approach for the prevention and/or treatment of autoimmune disease.

Amino Acid Sequence↗

PubMed1995

[The eae gene, adherence to HeLa cells and serotypes of Escherichia coli isolated from diarrhea].

We screened for the presence of Escherichia coli eae gene, one of the pathogenic factors of enteropathogenic E. coli (EPEC), by using the PCR method and compared the results with those from localized adherence to HeLa cells, presence of the EAF plasmid and the serotyping. One thousand one hundred and four E. coli strains isolated from diarrhea were examined, 144 (13.0%) possessed the eag gene. Of these eae positive strains, 93 (8.4%) exhibited localized adherence to HeLa cells and carried the EAF plasmid. And of these, 79 (7.2%) belonged to EPEC serotypes and 14 (1.3%) belonged to non-EPEC serotypes. Five (0.5%) with weak adherence, and 46 (4.2%) with no adherence were EAF plasmid negative. Predominant serotypes of EPEC were O55:H-, O86:H34, O111:H2, O119:H6, O128:H2 and main serotype of non-EPEC was O88:H25. Predominant serotypes of E. coli with no adherence to HeLa cells were O26:H-, O55:H-, O101:H-. EPEC and non-EPEC with localized adherence to HeLa cells were associated with diarrhea. Some of the eae positive strains with no adherence to HeLa cells, may have lost the EAF plasmid during storage. Though several variants of eae gene exist, it is necessary to confirm whether the strains possessing the eae gene without localized adherence to HeLa cells can cause diarrhea.

Bacterial Adhesion↗