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PubMed1995

2-Buten-4-olide (2-B4O) inhibits experimental allergic encephalomyelitis (EAE) in Lewis rats.

Starvation is well known to induce immune suppression. Moreover, the concentration of 2-B4O, an endogenous sugar acid, is elevated in the circulation during starvation. To determine if these events are related, the influence of 2-B4O on experimental allergic encephalomyelitis (EAE) in Lewis rats, a model of human multiple sclerosis (MS), was studied. EAE, characterized by paralysis of hind legs, was induced by immunization with residues 68 to 84 (MB 68-84) of the guinea pig myelin basic protein (MBP) in complete adjuvant H37Ra. Interestingly, the daily administration of 2-B4O intraperitoneally from the day of MB 68-84 immunization (day 0) to day 20 dramatically suppressed the clinical severity of EAE. The daily administration of 2-B4O intraperitoneally from day 0 to day 7 also markedly reduced the clinical symptoms of EAE. In fact, passively induced EAE, using Con A activated spleen cells from rats immunized with MB 68-84 in H37Ra, was also inhibited by daily administration of 2-B4O. Histological examination confirmed clinical findings and revealed that mononuclear cell infiltration into the central nervous system was significantly inhibited by 2-B4O. To clarify the mechanism(s) responsible for suppression of EAE, the effects of 2-B4O on the immune responses to MB 68-84 were examined. When rats were treated daily with 2-B4O for 15 days after immunization with MB 68-84 in H37Ra, the delayed-type hypersensitivity (DTH) response to MB 68-84 was significantly reduced in 2-B4O treated rats as compared with saline treated rats. The proliferative response to MB 68-84 of spleen cells from 2-B4O treated rats was also significantly lower than that of saline treated rats. Our data demonstrate that 2-B4O has the potential to suppress autoimmune responses in both inductive and effector phases. 2-B4O may have significant potential to treat autoimmune diseases.

4-Butyrolactone↗
PubMed2001

Role of MOG-stimulated Th1 type "light up" (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE).

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis in humans. EAE can be passively transferred into naive syngeneic animals by administration of MOG-specific T cell clones. Lymphocytes isolated from green fluorescent protein (GFP)-transgenic (Tg) mice can light up by emitting green fluorescence, thus making it feasible to use such animals in a passive transfer model for EAE. When MOG-sensitized splenic lymphocytes from GFP-Tg mice were adoptively transferred to irradiated, syngeneic C57BL/6 and RAG-1(-/-)mice, typical symptoms of EAE developed. Analysis of the reconstituted mice with EAE revealed prominent infiltration of fluorescing (GFP+), CD4+ T cells into the central nervous system (CNS). Real-time confocal imaging revealed these cells in the spinal cords and brains of recipient mice. This infiltration was also confirmed by anti-GFP monoclonal antibodies. Furthermore, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) evaluation indicated that the infiltrating GFP+, CD4+ T cells exclusively produced T helper type 1 (Th1) cytokines, especially interferon-gamma (IFN-gamma). These results clearly show that MOG-specific CD4+ T cells preferentially invade into the CNS and mediate the development of EAE by producing Th1-biased cytokines.

Adoptive Transfer↗
PubMed1984

Elicitation of experimental allergic encephalomyelitis (EAE) in mice with the aid of pertussigen.

Pertussigen, one of the biologically active proteins from Bordetella pertussis, was found highly active as an adjuvant to promote the induction of experimental allergic encephalomyelitis (EAE) in (SJL X BALB/c)F1 mice that had received at the same time an injection of mouse spinal cord (MSC) homogenized in complete Freund's adjuvant containing 4 mg of Mycobacterium tuberculosis H37RA per milliliter (CFA-H37). In this system 2 mg of MSC induced EAE, but a dose of 4 mg was more effective. As little as 250 ng of pertussigen facilitated induction of EAE, and 400 ng uniformly did so. Pertussigen was most effective when given iv from 1 day before to 5 days after administration of MSC homogenized in CFA-H37, when a uniform and severe disease was induced 11-13 days after immunization. Pertussigen given as late as 20 days after MSC-CFA-H37 still precipitated a mild form of EAE which appeared 8-12 days after the injection of pertussigen. When pertussigen was given 5 days after immunization, a chronic, nonfatal type of EAE was induced, and this persisted for the entire 74 days of observation. Histologic findings in the brain and spinal cord 15 days after sensitization in mice which received pertussigen and developed EAE showed perivascular infiltrates consisting mainly of mononuclear cells.

Animals↗
PubMed1984

IgM and IgG responses during chronic relapsing experimental allergic encephalomyelitis (r-EAE).

During chronic relapsing experimental allergic encephalomyelitis (r-EAE) in guinea pigs, serum IgM and IgG concentrations increased markedly early in disease. Serum IgM and IgG increased similarly in control animals immunized with Freund's incomplete adjuvant (FIA) and Mycobacterium tuberculosis (MT). In the chronic phase of r-EAE but not in control animals, elevated IgM was also found in central nervous system (CNS) extracts, suggesting intrathecal IgM synthesis. IgG antibodies against myelin and myelin basic protein (MBP) were regularly detected in r-EAE sera from day 21 post inoculation (p.i.), reaching maximum levels in the early chronic phase. IgG antibodies against galactocerebroside (GC) and galactose appeared in some r-EAE sera. Oligoclonal IgG bands were demonstrated in all r-EAE guinea pig sera 21-26 days p.i. The bands in serum decreased in number and strength in the chronic phase. They could be traced to antibodies against MT in 4 of 10 animals, but not to antibodies against myelin, MBP, GC or galactose. Oligoclonal IgG bands were also regularly visualized in r-EAE CNS 124 days p.i., suggesting persistent intrathecal IgG synthesis. They varied in number and migration between different regions of individual CNS. Oligoclonal CNS IgG was related to antibodies against MT in only one of 7 animals, and in no case to antibodies against myelin.

Animals↗
PubMed1996

Vaccination with peptides from MHC class II beta chain hypervariable region causes allele-specific suppression of EAE.

In our earlier studies we showed that successful immunotherapy of EAE in SJL/J mice can be achieved either by the use of antibodies to MHC class II antigens or by vaccination with synthetic peptide analogs of the beta chain of MHC class II molecules. We proposed that inhibition of EAE following vaccination with synthetic peptides derived from the beta chain of mouse I-A, was in part due to the generation of auto-anti-MHC class II antibodies that interfered with T cell sensitization. In our present study we show that suppression of EAE following vaccination results in poor sensitization of MBP reactive T cells, and that the lack of immune response is allele-specific. In F1(SJL(I-AS) x Balb/cI-Ad) mice, in which susceptibility to EAE is linked closely to the I-AS allele, vaccination with peptides from beta chain of I-AS results in inhibition of proliferative response to MBP and prevents the development of EAE. Vaccination with peptide from the beta chain of I-Ad did not affect either the development of immune response to MBP or the induction of EAE, indicating allele-specific suppression. Since global immunosuppression is not induced by vaccination with I-A peptides, we propose that this strategy can be extended to human autoimmune diseases wherein a clear association between certain MHC class II alleles and autoimmune disease is evident.

Alleles↗
PubMed2004

Converting relapsing remitting to secondary progressive experimental allergic encephalomyelitis (EAE) by ultraviolet B irradiation.

We induced experimental allergic encephalomyelitis (EAE) in SJL/J mice, an animal model for multiple sclerosis (MS), using myelin oligodendrocyte glycoprotein (MOG)(92-106) peptide, following ultraviolet (UV) irradiation. While all control mice developed relapsing-remitting (RR)-EAE, UV irradiation induced secondary progressive (SP)-EAE in some of the mice. Although mild demyelination was observed with T cell infiltration in RR-EAE, large demyelinating lesions developed in SP-EAE with massive macrophage and neutrophil infiltration and immunoglobulin deposition, but with little T cell infiltration. UV irradiation induced higher anti-MOG antibody responses. In SP-EAE, lymphoproliferative responses and interferon-gamma production were decreased without alteration of interleukin-4.

Amino Acid Sequence↗
PubMed2005

Bone marrow transplantation combined with gene therapy to induce antigen-specific tolerance and ameliorate EAE.

Hematopoietic stem cell (HSC) transplantation is a potential therapy that can offer multiple sclerosis patients a radical, potentially curative treatment. Using experimental autoimmune encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B cells expressing myelin basic protein (MBP), MBP Ac1-11, or myelin oligodendrocyte glycoprotein p35-55 induced tolerance and reduced symptoms. Here, we extend our tolerance approach using bone marrow (BM) cells expressing full-length phospholipid protein (PLP) in a model for relapsing, remitting EAE. Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks. Upon challenge, T cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol. In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol. Finally, the protective effect of PLP-expressing BM could also be observed using a nonmyeloablative protocol, albeit with lower efficacy. Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.

Animals↗
PubMed1999

IL-12 reverses the suppressive effect of the CD40 ligand blockade on experimental autoimmune encephalomyelitis (EAE).

Blockade of the CD40 ligand (CD40L)-CD40 interaction suppresses experimental autoimmune encephalomyelitis (EAE). Since this interaction induces IL-12, an essential cytokine for EAE induction, we hypothesized that CD40L blockade may suppress EAE through IL-12 inhibition. Here we show that exogenous IL-12 abolishes the ability of anti-CD40L monoclonal antibodies to prevent EAE. Anti-IL-12 antibodies prevent this reversal and protect from EAE. These results show that IL-12 is sufficient to overcome CD40L blockade and suggest that, of the multiple consequences of the CD40L-CD40 interaction, IL-12 induction is an essential one for induction of EAE.

Animals↗
PubMed2002

A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE.

Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.

Androstenes↗
PubMed2003

Typing of the eae and espB genes of attaching and effacing Escherichia coli isolates from ruminants.

The types of the eae and espB genes of 178 attaching and effacing Escherichia coli (AEEC) strains isolated from diarrhoeic and healthy ruminants were investigated by PCR. Six types of the eae gene: beta (beta), gamma1 (gamma-1), gamma2 (gamma-2), epsilon (epsilon), zeta (zeta) and iota (iota), and three types of the espB gene: alpha, beta and gamma were identified in the strains studied. Moreover, three strains were negative to all the types of the eae gene tested. The types beta and gamma2 in healthy cattle, beta, gamma2 and epsilon in healthy sheep and goats, and beta in diarrhoeic calves, lambs and goat kids were the most frequent types of the eae gene among the strains studied. Although the eaebeta gene was the most prevalent among AEEC from healthy and diarrhoeic ruminants, the percentages of AEEC strains with this type found in this study in diarrhoeic animals (66.7-100%) were higher than those found in healthy animals (33.3-40.6%). Thus, these data suggest that AEEC strains with the eaebeta gene are associated with neonatal diarrhoea in ruminants. The eaegamma1, eaezeta and eaeiota genes were found in low percentages in the strains studied (4.5, 2.8 and 7.3%, respectively). All the types of the eae gene, except the type iota, showed a close correlation with the types of the espB gene: the eaebeta and eae epsilon genes with the espBbeta gene, the eaegamma2 and eaezeta genes with the espBalpha gene and the eaegamma1 gene with the espBgamma gene.

Adhesins, Bacterial↗
PubMed1998

Neonatal handling in EAE-susceptible rats alters NGF levels and mast cell distribution in the brain.

Maternal separation in neonatal rodents causes a wide range of behavioural and metabolic alterations, affecting the physiological response of the neuro-immune-endocrine system. For example, interference with the normal mother-infant interactions leads to an increased susceptibility to experimentally-induced allergic encephalomyelitis (EAE) in adult life. Since it has been reported that mast cells (MCs) participate in the pathophysiology of the autoimmune inflammatory disease multiple sclerosis (MS) and also EAE and that brain nerve growth factor (NGF) levels are altered in EAE, studied whether maternal separation and gentle manipulation (gentling) of neonatal Lewis rats perturb NGF levels or MC distribution in the brain. EAE-induction susceptibility in adult life was also evaluated and NGF levels and mast cell distribution within the hippocampus and thalamus were measured at 0, 10, 20 and 60 postnatal days. Our results show an exacerbation of clinical signs in rats separated from mothers where EAE was induced, a general decrease in NGF protein levels and MC number in the hippocampus during the first developmental period and significant increase in the number of MC in the hippocampus and the thalamus at young-adulthood (60 days of age). These results indicate that disruption of the maternal bond during early infancy may produce long-lasting alterations in the brain cellular and molecular environment, leading to increased susceptibility to EAE in adult life.

Animals↗
PubMed1996

Aggravation of experimental allergic encephalomyelitis (EAE) by administration of nitric oxide (NO) synthase inhibitors.

Macrophages constitute a large proportion of the inflammatory cells that infiltrate the central nervous system (CNS) of animals with EAE. Through the production of inflammatory mediators these infiltrating macrophages can contribute to the regulation of the immune reaction within the CNS, that eventually results in neurological deficits associated with EAE. NO, a free radical produced by macrophages and other cell types, has been put forward as such an immune mediator. In the present study we show that macrophages isolated from the CNS of Lewis rats with clinical signs of EAE produce elevated amounts of NO. We treated rats, in which EAE was induced, with N(omega) -nitro-L-arginine-methylester or N(g)-monomethyl-L-arginine, inhibitors of NO synthase, either systemically via intraperitoneal injection, or intracerebrally via a cannula placed in the lateral ventricle. Both treatments resulted in a marked aggravation of clinical signs of EAE. These data point to an important role of NO, produced by infiltrating macrophages, as an immune-suppressor in the disease process during EAE.

Animals↗
PubMed2006

Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE.

Inflammation results in CNS damage in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. It is uncertain how much repair of injured myelin and axons can occur following highly selective anti-inflammatory therapy in EAE and MS. In this study, SJL/J mice with established EAE were treated successfully with an antigen-specific recombinant T cell receptor ligand (RTL), RTL401, a mouse I-A(s)/PLP-139-151 construct, after the peak of EAE. To define the mechanisms by which late application of RTL401 inhibits EAE, we evaluated mice at different time points to assess the levels of neuroinflammation and myelin and axon damage in their spinal cords. Our results showed that RTL401 administered after the peak of acute EAE induced a marked reduction in inflammation in the CNS, associated with a significant reduction of demyelination, axonal loss and ongoing damage. Electron microscopy showed that RTL-treated mice had reduced pathology compared with mice treated with vehicle and mice at the peak of disease, as demonstrated by a decrease in continued degeneration, increase in remyelinating axons and the presence of an increased number of small, presumably regenerative axonal sprouts. These findings indicate that RTL therapy targeting encephalitogenic T cells may promote CNS neuroregenerative processes.

Animals↗
PubMed1997

Cloning and characterization of the eae gene from a dog attaching and effacing Escherichia coli strain 4221.

We have cloned and determined the nucleotide sequence of the eae gene from a dog attaching and effacing (A/E) Escherichia coli (DEPEC) strain 4221. When comparing the predicted amino acid sequence of the eaeDEPEC to that of the Eae proteins from enteropathogenic E. coli (EPEC), enterohaemorrhagic E. coli O157:H7 (EHEC), Citrobacter freundii biotype 4280, and a swine A/E E. coli strain O45 (PEPEC), the overall sequence identity was 84, 81, 83 and 83%, respectively, with the greatest divergence at the C-terminal end, the putative receptor-binding portion. Interestingly, the DEPEC Eae shares the greatest identity at the C-terminal region with the Citrobacter freundii Eae protein. We have constructed and purified a maltose-binding fusion protein (MBP) containing the product of the entire eae gene of the DEPEC strain 4221. Binding of MBP-EaeDEPEC fusion protein to HEp-2 cells was demonstrated by immunofluorescence microscopy. In addition, the Eae protein of DEPEC (4221) demonstrated a strong serological relationship with that of EPEC (E2348/69) as observed using a polyclonal antiserum against MBP-EaeDEPEC fusion protein.

Adhesins, Bacterial↗
PubMed1993

Detection and characterization of the eae gene of Shiga-like toxin-producing Escherichia coli using polymerase chain reaction.

In this study, the polymerase chain reaction (PCR) was used in the detection of the attaching and effacing (eae) gene of Shiga-like toxin-producing Escherichia coli (SLT-EC). Oligonucleotide primers, complementary to the 5' portion of the eae gene of the enteropathogenic E. coli E2348/69 (O127:H6) and of SLT-EC CL8 and EDL933 (O157:H7), generated PCR products of the predicted sizes with DNA from the majority of human clinical SLT-EC strains tested from O serogroups 5, 26, 103, 111, 121, 128, 145, and 157; all SLT-EC strains of O serogroups 5, 26, and 111 from cattle; and a minority of porcine SLT-EC strains (one strain each from O serogroups 107 and 130 and one rough strain). Five HaeIII digestion profiles were obtained for PCR products generated by amplification of a 2.3-kb DNA fragment from the 5' end of eae. The HaeIII profiles for SLT-EC O serogroups, such as 26, 103, and 157, differed from each other but were consistent among strains within these O serogroups. Oligonucleotide primer pairs complementary to the 3' end of either the O127:H6 E. coli or the O157:H7 eae nucleotide sequence only amplified DNA from E. coli strains from a few of the SLT-EC O serogroups examined. One primer pair with homology to the 3' nucleotide sequence of eae from E. coli O157:H7 appeared to be relatively specific for this O serogroup by PCR. No PCR products were obtained in amplification experiments with the eae primers using DNA from human SLT-EC of O serogroups 38 (1 0f 1) and 91 (3 or 3), 15 of 15 SLT-EC strains from edema disease, or 29 of 29 non-SLT-EC strains from pigs and calves with diarrhea.

Bacterial Adhesion↗
PubMed1993

The role of the eae gene of enterohemorrhagic Escherichia coli in intimate attachment in vitro and in a porcine model.

The eaeA gene of enteropathogenic Escherichia coli (EPEC) is necessary for intimate attachment to epithelial cells in vitro. Enterohemorrhagic E. coli (EHEC) strains also possess an eae gene and are capable of intimate attachment and microvillus effacement in vitro and in animal models. To assess the role of the EHEC eae gene in intimate attachment, we constructed an eae deletion/insertion mutation in wild-type EHEC O157:H7 strain 86-24 by using linear electroporation of a recombinant allele. The mutant obtained was deficient in inducing f-actin accumulation in HEp-2 cells and was incapable of attaching intimately to colonic epithelial cells in a newborn piglet model of infection. Intimate attachment in vivo was restored when the EHEC eae gene or the eaeA gene of EPEC was introduced into the mutant on a plasmid. These results indicate that the eae gene is necessary for intimate attachment of EHEC in vivo. In addition, the complementation achieved by the EPEC locus indicates that the eae gene of EHEC and the eaeA gene of EPEC are functionally homologous.

Adhesins, Bacterial↗
PubMed1990

Differential susceptibility to experimental allergic encephalomyelitis (EAE) in genetically defined A+ and A- rabbits.

Only one out of 57 A-/A- rabbits immunized with rat or guinea-pig myelin developed clinical signs suggestive of EAE. On the contrary, clinical signs of acute or chronic EAE were found in two thirds of the 102 A+/A+ and A+/A- rabbits immunized in the same way. About one third of the diseased animals had reversible acute EAE, another third died paralysed and the last third developed chronic progressive or relapsing EAE. Incidence and severity of EAE symptoms were positively correlated with age and no significant difference was observed between males and females. Cellular and humoral anti-myelin responses were stronger in A+ than in A- rabbits. Anti-A antibodies, on the contrary, were only detected in A- rabbits. The A+ rabbits did not make Anti-A at any time. Anti-A antibodies increased early, in A- rabbits, after immunization with myelin (11-30 days) and were later replaced by a low, but specific, anti-myelin response (60-90 days). The gene responsible for the susceptibility to EAE is autosomal and dominant over resistance. This gene must be closely linked to the A locus or might be the A gene itself. The low susceptibility of A- rabbits to the disease could be, in this last case, a consequence of the competition between the early anti-A and the normal anti-myelin immune responses, both induced by the injection of myelin.

ABO Blood-Group System↗
PubMed2002

Phenotypes of T cells infiltrating the eyes in autoimmune anterior uveitis associated with EAE.

PURPOSE: Lewis rats immunized with myelin basic protein (MBP) develop experimental autoimmune encephalomyelitis (EAE) and associated anterior uveitis (AU), which recurs. The goal was to analyze cellular activation markers and adhesion molecules of T cells that infiltrate the eyes and spinal cord during acute and recurrent AU in actively and passively induced diseases simultaneously in the same animals. METHODS: EAE-AU was induced in Lewis rats by immunization with MBP in CFA, or by adoptive transfer of MBP-specific T-cell lines, and the signs of clinical EAE and AU was scored. Cells isolated from the iris-ciliary body were tested by flow cytometry for expression of CD4, CD8, CD45RC, T-cell receptor (TCR) Vbeta8.2, alpha4 integrin, L-selectin, CD44, and CD134. RESULTS: Ocular T cells showed a significantly higher expression of CD62L (l-selectin) than did T cells in the spinal cord. In addition, a much lower percentage of infiltrating CD8(+) T cells was found in the eyes during AU. In passive transfer experiments, T-cell lines derived from acute and recurrent uveitis showing similar phenotypes differing in specificities but possessed the capacity of inducing both AU and EAE. Pretreatment of rats with effector CD4(+) T cell before MBP immunization did not induce suppression of EAE or AU. However, pretreatment with regulatory CD8(+) T cells significantly reduced the severity and duration of both EAE and AU. CONCLUSIONS: T cells recruited into the inflamed eyes or central nervous system (CNS) are mainly activated/memory T cells expressing different levels of L-selectin. Regulatory CD8(+) T cells may contribute to the susceptibility of the eye to recurrent AU. The differences in phenotypes of T cells recruited simultaneously to two different organs suggest that microenvironment also plays a role in determining lymphocyte homing.

Adoptive Transfer↗