Biomedical subjects

E Beraud

Publications and source records attributed to E Beraud.

16 recordsLinked to original sources

PubMed1999

A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis.

Myelin basic protein (MBP), is a major component of the central nervous system (CNS) myelin. MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. EAE is an inflammatory and demyelinating autoimmune disease of the CNS that serves as a model for the human disease Multiple Sclerosis (MS). Taking advantage of the fact that EAE can be mediated by T cells, able to recognize MBP or its peptides, we developed a new approach to target anti-MBP T cells by fusing an MBP-sequence to a toxin. In the new chimeric protein, an oligonucleotide coding for the guinea pig MBP encephalitogenic moiety (residues 68-88) was fused to a cDNA encoding a truncated form of the PE gene (PE40). The chimeric gene termed MBP-PE was expressed in E. coli and highly purified. MBP-PE chimeric protein was cytotoxic to various anti-MBP T cells. Moreover, treatment with the novel MBP-toxin blocked the clinical signs of EAE as well as CNS inflammation and demyelination. A chimeric protein such as MBP-PE40 presents a novel prototype of chimeric proteins, composed of antigen/peptide-toxin, that could prove to be an efficient and specific immunotherapeutic agent for autoimmune diseases in which a known antigen is involved.

ADP Ribose Transferases↗

PubMed1993

Pathogenic and non-pathogenic T lymphocytes specific for the encephalitogenic epitope of myelin basic protein: functional characteristics and vaccination properties.

Activated CD4+ T lymphocytes specific for myelin basic protein (MBP) can cause experimental autoimmune encephalomyelitis (EAE) upon their inoculation into syngeneic recipients. In Lewis rats, most of the pathogenic T cell clones that develop following immunization with MBP are reactive against the 72-84 amino acid sequence of MBP, the major encephalitogenic region for Lewis rats. In this study, some MBP-specific T cell clones were found to be non-pathogenic, in spite of their strong reactivity against the encephalitogenic epitope. One of these non-pathogenic clones, designated Znp, and an encephalitogenic clone, Z1a-p, were derived from Z1a encephalitogenic line cells. These subclones were compared for epitope specificity, T cell receptor variable gene expression and for various functional activities, in order to delineate properties crucial for pathogenicity. The Z1a-p and Znp cells expressed comparable levels of the T cell receptor genes and shared strong reactivity against the 72-84 epitope of MBP. The pathogenic Z1a-p cells displayed MBP-specific cytolytic activity in vitro, provided an in-vivo 'help' for elicitation of MBP-specific antibodies, mediated a delayed type hypersensitivity (DTH) response to MBP, caused EAE and vaccinated against the disease, thus demonstrating that a single CD4+ T cell clone is capable of eliciting various functions. The non-pathogenic Znp cells could also carry out most of these various functions, but failed to mediate a DTH response to MBP in normal animals. However, when inoculated into sublethally (650 R) irradiated syngeneic recipients, the Znp cells became highly pathogenic and mediated DTH response to MBP. Local irradiation of the recipient facilitated a DTH response to MBP in the irradiated ear, indicating that Znp cells are equipped with the effector mechanisms required for pathogenicity, and that their failure to cause disease may be accounted for by their inability to migrate into extravascular target tissue. Similar data were obtained with an independently isolated non-pathogenic clone, LB-3, specific for the encephalitogenic epitope of MBP. The ability of these non-pathogenic cells to vaccinate against EAE mediated by pathogenic cells raises the possibility that such non-pathogenic cells may play a role in triggering downregulation of pathogenic T cells.

Animals↗

PubMed1992

Control of experimental autoimmune uveoretinitis by low dose T cell vaccination.

Autoimmune T lymphocytes can be used under appropriate conditions to induce resistance to the specific autoimmune disease that they usually produce. This practice, termed T cell vaccination, was found to be effective with the injection of a low (subpathogenic) number of autoaggressive T line lymphocytes. We report here that T cell vaccination produced marked resistance to the expression of experimental autoimmune uveoretinitis (EAU) in Lewis rats. In addition, vaccination led to the appearance of lymphoid cells in the vaccinated rats that demonstrated proliferative responses against idiotypic and ergotypic specificities of the injected T cells. This is the first report demonstrating the effector T lymphocytes specific for ocular antigens may be used as agents to modulate immunopathogenic responses responsible for EAU.

Amino Acid Sequence↗

PubMed1991

T cell vaccination in autoimmune diseases.

The effectiveness and the mechanism of T cell vaccination were studied in two experimental models of autoimmune disease. The attempt to modulate autoimmune disease via idiotypic regulation of autoreactive antigen-specific T cells was first shown in the rat experimental autoimmune encephalomyelitis (EAE) model where inactivated EAE-inducing T cells could both immunize and protect rats from EAE. We previously reported that low dose T cell vaccination against EAE in Lewis rats was immunologically specific, long lasting and extremely efficient in preventing adoptive transfer of the disease. In experimental autoimmune uveitis (EAU) T cell vaccination was also found to be effective. In both cases, antigen or mitogen activation of the T cells prior to inoculation was required. In the EAE model, T cell vaccination appeared to be associated with two sets of T lymphocytes (CD4+ CD8- helper and CD4- CD8+ cytotoxic/suppressor cells) which were cloned and found to be specifically reactive to the vaccine cells. These anti-idiotypic T cell clones were able to antagonistically modulate the in vitro proliferation of encephalitogenic Z1a cells. In vivo, transfer of the lymph node cells (from which the anti-idiotypic clones were derived) from vaccinated animals to naive syngeneic recipients conferred resistance to EAE. In the EAU model, we also found a consistent immunological response raised against different activated T cells (four T cell lines with irrelevant specificities and mitogen-activated lymphoid cells) in addition to the anti-idiotypic cells. This response, apparently directed to T cell activation markers, might combine with the anti-idiotypic response to regulate autoimmunity.

Animals↗

PubMed1991

Immunospecific suppression of encephalitogenic-activated T lymphocytes by chimeric cytotoxin IL-2-PE40.

We examined the action of a chimeric protein, IL-2-PE40, on the development of a T cell-mediated disease of the central nervous system with numerous similarities to multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). EAE is caused by IL-2 receptor-bearing T cells specific for myelin basic protein (BP). We report here that the treatment of Lewis rats with IL-2-PE40 delayed and shortened the course of EAE induced by BP in adjuvant and dramatically prevented EAE mediated by anti-myelin basic protein T line cells. The absence of paralytic signs, the absence of cell infiltration in the central nervous system, and the abatement of cellular immunity to myelin basic protein in the treated rats are direct consequences of the specific mechanism of action of IL-2-PE40. Our data support the notion that IL-2-PE40 may be efficient as an immunosuppressive agent for those disorders in which activated T cells play a crucial role.

ADP Ribose Transferases↗

PubMed1991

T cell receptor beta-chain usage in experimental autoimmune uveoretinitis.

Genomic rearrangements to the T-cell receptor (TCR) V beta 8 gene locus were examined in T cells derived from the lymph nodes of Lewis rats immunized with either S-Antigen or peptides derived from interphotoreceptor retinoid binding protein (IRBP). The cells used in these studies are from T-cell lines that have been selected by several cycles of antigen/IL-2 stimulations, or clones isolated from these lines. No apparent rearrangement of the V beta 8 gene was observed by Southern analysis, suggesting that if indeed there are T cells using V beta 8 gene elements they represent small proportions of the cells in these T-cell lines that induce EAU (uveitogenic T cells) and that the lines may consist of large numbers of clones. On the other hand, we have demonstrated V beta 8 gene expression in uveitogenic T-cell populations by Northern analysis and by polymerase chain reaction (PCR). Although V beta 8 gene transcripts were detectable in pathogenic, but not in non-pathogenic, T-cell lines using a V beta 8 cDNA probe, RNA from pathogenic T cell lines did not hybridize to another probe specific for rat V beta 8.2. Taken together, these results suggest that, unlike the T-cell lines that mediate experimental allergic encephalomyelitis (EAE), some T-cell lines that induce EAU do not predominantly express V beta 8.2 gene but other member(s) of the V beta 8 family.

Animals↗

PubMed1990

Multiple sclerosis: cell-mediated immunity to human brain gangliosides.

Cell-mediated immunity (CMI) to myelin components has been implicated in Multiple Sclerosis (MS) pathogenesis: two targets were suggested, Myelin Basic Protein with controversial results and, more recently, gangliosides. In order to investigate their possible involvement, we have performed Leukocyte Migration inhibition (LMI) tests in the presence of human brain gangliosides. Thirty nine MS patients (twenty four being "definite", according to McDonald and Halliday's classification), twenty nine patients with Other Neurological Diseases (OND), thirty six patients with Inflammatory diseases (ID) and forty healthy controls were tested. MS patients were divided into two groups, depending on the clinical stage of the disease. The mean migration inhibition percentage of the MS-attack group was found to be significantly different from the four others (p less than 0.01) (24.4 +/- 16.2 versus 10.9 +/- 8.5 in MS without attack, 4.4 +/- 12.9 in OND, 3.9 +/- 13.9 in ID and 11.1 +/- 12.1 in healthy subjects). LMI to gangliosides is therefore significantly increased during the attack stage in MS. These results support the notion of a Delayed Type Hypersensitivity to these glycolipids during the active stage of the disease.

Adult↗

PubMed1989

Vaccination against experimental autoimmune encephalomyelitis using a subencephalitogenic dose of autoimmune effector cells (1). Characteristics of vaccination.

We previously reported that rats could be vaccinated against EAE by inoculation with 10(7) anti-basic protein (anti-BP)-activated T cells raised as long-term lines. The activated T lines were irradiated (1,500 rads) to prevent them from causing EAE. We now report that a single inoculation of 10(4) or fewer cells of an activated anti-BP T-cell line did not cause clinical EAE but rather induced marked resistance to EAE produced by adoptive transfer of the anti-BP T cells. Resistance was less effective against EAE induced by active immunization to BP. Vaccination was immunologically specific, long lasting, and could be effected by various routes of administration.

Animals↗

PubMed1989

Vaccination against experimental autoimmune encephalomyelitis using a subencephalitogenic dose of autoimmune effector T cells. (2). Induction of a protective anti-idiotypic response.

We previously reported that a subencephalitogenic dose (10(4) of activated anti-BP Z1a T cells rendered Lewis rats significantly resistant to EAE induced either actively or adoptively. This resistance was specific to EAE and persisted for over 4 months. The experiments reported in this paper were done to investigate the mechanisms of this resistance. We found that the state of vaccination was marked by a decrease in the in vitro proliferation and in vivo DTH responses to BP. Resistance could be transferred to recipient rats with the thymus or spleen cells of donor vaccinated rats. Vaccination led to the appearance of proliferative and DTH responses that were specifically directed to the Z1a T cells. The kinetics and compartmentalization of this anti-idiotypic responsiveness was studied by vaccinating rats in the hind footpads and monitoring the proliferative reactivity of the draining popliteal lymph node (PLN) and distal cervical lymph node (CLN) cells at various times. We found that the anti-idiotypic reactivity was confined to the PLN on days 5-6 and thereafter became systemic. Excision of the PLN on day 6, but not on days 3 or 11, robbed the rats of their acquired resistance to EAE. In contrast, the PLN cells of the vaccinated rats transferred resistance to naive donors. Thus, the lymphoid population containing cell-mediated anti-idiotypic responsiveness served as a vehicle of resistance. These results suggest that anti-idiotypic T-cell immunity to autoimmune effector T cells is involved in the resistance to EAE induced by T-cell vaccination.

Animals↗

PubMed1989

Absence of major histocompatibility complex restriction in the interaction between processed basic protein and Ia of two rat strains.

Antigen fragments, biologically degraded by antigen-presenting cells (APC), combine with Ia positive moieties (IPM) to stimulate antigen-specific T lymphocyte lines. The main objective of this study was to evaluate whether this interaction was determined by the major histocompatibility complex (MHC) genotype of the APC, thus genetically restricting antigen-specific T lymphocyte proliferative responses. To do so, we assayed the capacity of processed basic protein, associated with IPM, to stimulate basic protein specific T lymphocyte lines derived from the Lewis (LW), Brown Norway (BN), and (LW x BN)F1 rat strains. Our findings are that: (a) IPM replaced the requirement for intact APC in proliferative responses of T lymphocytes to processed basic protein; (b) processed basic protein, irrespective of the genotype of APC from which it was prepared, was fully reconstituted by all IPM genotypes tested. Hence, the interaction between processed antigen and IPM was not found to be MHC-restricted. The possible implication of this conclusion is discussed.

Animals↗

PubMed1988

Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis.

In a study of the mechanism of resistance to autoimmune disease induced by T cell vaccination, rats were vaccinated against experimental autoimmune encephalomyelitis (EAE) by injecting them once in the hind footpads with a subencephalitogenic dose (10(4)) of a clone of T lymphocytes specific for myelin basic protein (BP). The response to vaccination was assayed by challenging the rats with an encephalitogenic dose (3 X 10(6)) of T lymphocytes of this BP-specific clone. Five to six days after vaccination, the cells responsible for mediating resistance to adoptively transferred EAE were concentrated in the popliteal lymph nodes draining the vaccination site. Transfer of the draining lymph node cells to unvaccinated rats led to loss of resistance in the donor rats and acquisition of resistance by the recipient rats. Limiting-dilution cultures of the draining lymph node cells were established with irradiated cells of the BP-specific clone as stimulators. Two sets of T lymphocytes specifically responsive to the BP-specific T cells from the clone were isolated: CD4+CD8- helper and CD4-CD8+ suppressor cells. The helper T cells, like the BP antigen, specifically stimulated the BP-specific vaccinating clone. In contrast, the suppressor T cells specifically suppressed the response of the BP-specific vaccinating clone to its BP antigen. These results suggest that T cell vaccination induces resistance to autoimmune disease by activating an antiidiotypic network.

Animals↗

PubMed1987

[Experimental autoimmune encephalomyelitis: immunoregulation and genetic control].

EAE is a good model of autoimmune diseases and an approximate one of MS, particularly in its chronic recurrent and demyelinating forms. The antigenic target of EAE has recently been better defined: in different species, as well as within a given one, the encephalitogenic determinant, target of T effector cells, is located in different parts of the basic protein of myelin. The recognition of the relevant epitope is influenced by the genotype of the antigen presenting cells. By analogy, in MS, one can expect to find various target-antigens for the immune (autoimmune?) reactions that occur in the Central Nervous System of different patients, may be in correlation with HLA phenotype. The study of immunoregulatory processes in EAE suggests a possible role for suppressor cells and for variations in the capacity of interleukin-2 production. Similarly, in MS, variations in suppressor cell activities have been found in acute attacks. Finally, the possibility of "vaccinating" against EAE with attenuated encephalitogenic line cells, opens new interesting perspectives in the therapy of MS.

Animals↗

PubMed1986

Experimental autoimmune encephalomyelitis mediated by T lymphocyte lines: genotype of antigen-presenting cells influences immunodominant epitope of basic protein.

Lewis rats are susceptible to experimental autoimmune encephalomyelitis (EAE), and their T lymphocytes recognize epitopes in the 68-88 sequence of guinea pig myelin basic protein (BP). BN rats are resistant to EAE, and their T lymphocytes recognize epitopes outside of the 68-88 sequence, probably in the 43-67 portion of BP. To investigate the influence of the genome of antigen-presenting cells (APC) on the dominance of BP epitopes for T lymphocyte lines, we selected anti-BP lines from (Lewis X BN)F1 rats by using the APC of Lewis, BN, or F1 origin. We now report that the F1/Lewis and F1/F1 lines recognized the 68-88 epitopes and were highly encephalitogenic in F1 rats, whereas the F1/BN line recognized the 43-67 epitopes and was only weakly encephalitogenic. Thus, the genotype of the APC can influence the immunologic dominance for T lymphocytes of BP epitopes, and this dominance in turn can influence the expression of disease.

Animals↗

PubMed1982

Suppressor cells in Lewis rats with experimental allergic encephalomyelitis: prevention of the disease and inhibition of lymphocyte proliferation by the suppressor cells or their products.

Lewis rats primed with myelin basic protein (MBP) in complete Freund's adjuvant develop experimental allergic encephalomyelitis (EAE) and suddenly recover 15 to 17 days later. It was previously found that nondraining lymph node (non-DLN) cells taken at the time of convalescence and transferred into syngeneic normal animals inhibit the subsequent induction of EAE. In this report, it is shown that a suppressive factor can be extracted from non-DLN cells which mimics the inhibitory effect of cells when injected into the recipients. Non-DLN cells keep their suppressive activity on the induction of EAE after a culture of 48 h but their supernatant of culture failed to exert any protective effect in vivo. However, in vitro both the culture supernatant and the suppressor cells were found to have an inhibitory effect on the proliferative response of immune lymphoid cells to the antigen (MBP).

Animals↗

PubMed1977

Evidence for suppressor cells in Lewis rats' experimental allergic encephalomyelitis.

In this work we demonstrate a suppressive activity on the induction of experimental allergic encephalomyelitis (EAE) in Lewis rats, transferable to syngeneic animals, challenged with encephalitogenic mixture (myelin basic protein, complete Freud's adjuvant plus Bordetella pertussis organisms) 24 h later. This activity is probably effected by T cells and not by (an) inhibitory serum factor(s). The induction of this specific protection could be due to the penetration of the myelin basic protein antigen into the thymus where we first found suppressive cells. From the thymus, suppressor cells could then emigrate to spleen (on day 15) and to nondraining lymph nodes (on day 17). In the course of normal EAE in Lewis rats and especially at the time of self cure, this suppression is not demonstrated, but possible.

Animals↗

PubMedDate not supplied

[Suppressor cells in allergic encephalomyelitis].

The induction of EAE in Lewis rats by basic protein (BP) is suppressed by the transfer of non-draining lymphnode cells from cured animals. The activation of draining lymphnode cells of these cured animals by BP, PHA or ConA is decreased with the addition of non-draining lymph node cells from the same rats.

Animals↗