scholarly journals Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice.

1988 ◽  
Vol 168 (1) ◽  
pp. 213-227 ◽  
Author(s):  
D H Kono ◽  
J L Urban ◽  
S J Horvath ◽  
D G Ando ◽  
R A Saavedra ◽  
...  
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Autoimmune Disease ◽  
Basic Protein ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
T Helper ◽  
Allergic Encephalomyelitis ◽  
Peptide Region ◽  
Experimental Allergic

Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS) that occurs after immunization of animals with myelin basic protein (MBP). The disease is a prototype model for the study of antigen-specific T helper cell-mediated autoimmune disease. In SJL/J mice, EAE is mediated by T helper cells directed against a 40-amino acid COOH-terminal peptic fragment of mouse small MBP. To identify the minimal T cell epitopes of MBP responsible for EAE, overlapping peptides completely encompassing the epitopes within this region were synthesized. A 28-residue peptide of mouse MBP spanning residues 87-114 (pM87-114) was able to elicit both a strong T cell response and chronic relapsing disease. To better localize the T cell epitopes, shorter peptides within this region were synthesized and two overlapping peptides, pM87-98 and pM91-104, were able to induce EAE. T cell clones and bulk lymph node cell populations reactive with pM87-98 did not respond to pM91-104. However, lymph node cells reactive with pM91-104 also reacted with pM87-98, thus showing that these two peptides represent contiguous, but distinct encephalitogenic epitopes and that both these epitopes may be contained within pM87-98. In addition, pM87-114 and pM87-98 were found to be minor determinants of the total T cell response to rat and rabbit MBP. The restricted response to MBP in SJL/J mice is similar to that of the PL/J mice in that each appears to have only a single peptide region in MBP that elicits encephalitogenic T cells. However, within the region studied, there were two if not more T cell epitopes. This differs from the single encephalitogenic PL/J epitope. These findings of a single encephalitogenic peptide region with multiple T cell epitopes and the fact that encephalitogenic T cell epitopes may be subdominant have implications for the design of treatments directed at the T cell receptor-MHC-peptide epitope complex in autoimmune disease.

scholarly journals The immune response against myelin basic protein in two strains of rat with different genetic capacity to develop experimental allergic encephalomyelitis.

1975 ◽  
Vol 141 (1) ◽  
pp. 72-81 ◽  
Author(s):  
D E McFarlin ◽  
S C Hsu ◽  
S B Slemenda ◽  
F C Chou ◽  
R F Kibler
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Experimental Allergic Encephalomyelitis ◽  
Cell Response ◽  
Basic Protein ◽  
T Cell Response ◽  
Skin Tests ◽  
Allergic Encephalomyelitis ◽  
Experimental Allergic

After challenge with guiena pig basic protein (GPBP) Lewis (Le) rats, which are homozygous for the immune response experimental allergic encephalomyelitis (Ir-EAE) gene, developed positive delayed skin tests against GPBP and the 43 residue encephalitogenic fragment (EF); in addition, Le rat lymph node cells (LNC) were stimulated and produced migration inhibitory factor (MIF) when incubated in vitro with these antigens. In contrast Brown Norway (BN) rats, which lack the Ir-EAE gene, did not develop delayed skin tests to EF and their LNC were not stimulated and did not produce MIF when incubated in vitro with EF. These observations indicate that the Ir-EAE gene controls a T-cell response against the EF. Le rats produced measurable anti-BP antibody by radioimmunoassay after primary challenge. Although no antibody was detectable in BN rats by radioimmunoassay, radioimmunoelectrophoresis indicated that a small amount of antibody was formed after primary immunization. After boosting intraperitoneally, both strains of rat exhibited a rise in anti-BP antibody; which was greater in Le rats. In both strains of rat the anti-BP antibody reacted with a portion of the molecule other than the EF. Since EF primarily evokes a T cell response, it is suggested that the EF portion of the BP molecule may contain a helper determinant in antibody production.

scholarly journals Peptide-specific prevention of experimental allergic encephalomyelitis. Neonatal tolerance induced to the dominant T cell determinant of myelin basic protein.

1989 ◽  
Vol 169 (5) ◽  
pp. 1681-1691 ◽  
Author(s):  
J P Clayton ◽  
G M Gammon ◽  
D G Ando ◽  
D H Kono ◽  
L Hood ◽  
...  
Keyword(s):  
T Cell ◽  
Autoimmune Disease ◽  
Myelin Basic Protein ◽  
Experimental Allergic Encephalomyelitis ◽  
Basic Protein ◽  
Disease Incidence ◽  
Cell Epitope ◽  
Allergic Encephalomyelitis ◽  
Significant Difference ◽  
Experimental Allergic

Experimental allergic encephalomyelitis (EAE) is a model of antigen-specific T cell-mediated autoimmune disease. The alpha-acetylated, NH2-terminal nine amino acids (1-9NAc) of myelin basic protein (MBP) represents the dominant T cell epitope for the induction of EAE in the B10.PL (H-2u) strain. We tolerized neonatal B10.PL mice to 1-9NAc and studied the proliferative responses to this peptide and to whole MBP. Mice exposed to 1-9NAc in the neonatal period were tolerant to subsequent challenge at the proliferative T cell level. Similarly, in the 1-9NAc-tolerant group, both the incidence and severity of 1-9NAc induced EAE were greatly reduced. The fact that we were able to tolerize mice normally responsive to MBP suggests that this self antigen is sequestered (within the central nervous system) and hence tolerance to it is not normally induced. No significant difference in disease incidence was seen in response to rat MBP between control animals and 1-9NAc-tolerized mice (50% in both groups), demonstrating the presence of at least one additional encephalitogenic determinant elsewhere on the molecule. We have successfully prevented disease induction by peptide-induced tolerization. Tolerance induction by peptides provides a new and specific strategy in the prevention of autoimmunity. However, it will be clearly necessary to fully define all epitopes potentially capable of inducing pathogenic T cells to ensure complete and effective therapy of T cell-mediated autoimmune disease.

T cell receptors in autoimmune disease as targets for immune intervention

Genome ◽  
1989 ◽  
Vol 31 (2) ◽  
pp. 656-661 ◽  
Author(s):  
Hans Acha-Orbea ◽  
L. Steinman ◽  
H. O. McDevitt
Keyword(s):  
T Cell ◽  
Autoimmune Disease ◽  
T Cell Receptor ◽  
Experimental Allergic Encephalomyelitis ◽  
Antibody Therapy ◽  
Cell Receptor ◽  
Allergic Encephalomyelitis ◽  
Immune Intervention ◽  
Receptor Antibodies ◽  
Experimental Allergic

The optimal form of treatment for an autoimmune disease should be highly specific, have few side effects, and allow treatment of clinically apparent disease. One target that could fulfill these requirements is the T cell receptor. To answer the question whether treatment of autoimmune disesase is possible with anti-T cell receptor antibodies, the heterogeneity of T cell receptor elements utilized in the T cell mediated autoimmune disease experimental allergic encephalomyelitis was analyzed. The limited heterogeneity of these elements allowed prevention and treatment of clinical autoimmune disease with anti-T cell receptor monoclonal antibodies. These results and their potential value for other autoimmune diseases are discussed.Key words: T cell receptor, autoimmune disease, monoclonal antibody therapy, experimental allergic encephalomyelitis.

scholarly journals IL-12 unmasks latent autoimmune disease in resistant mice.

1996 ◽  
Vol 184 (2) ◽  
pp. 771-775 ◽  
Author(s):  
B M Segal ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Immune Responses ◽  
Experimental Allergic Encephalomyelitis ◽  
Basic Protein ◽  
Inbred Mice ◽  
Allergic Encephalomyelitis ◽  
Ifn Gamma ◽  
Th 1 ◽  
Experimental Allergic

Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases.

scholarly journals Anti I-A antibody suppresses active encephalomyelitis: treatment model for diseases linked to IR genes.

1983 ◽  
Vol 158 (4) ◽  
pp. 1362-1367 ◽  
Author(s):  
S Sriram ◽  
L Steinman
Keyword(s):  
Autoimmune Disease ◽  
Basic Protein ◽  
Clinical Course ◽  
Treated Group ◽  
Gene Products ◽  
Allergic Encephalomyelitis ◽  
Chronic Relapsing Eae ◽  
Antibody Levels ◽  
Experimental Allergic ◽  
Ir Genes

To test the clinical relevance of monoclonal anti-I-A antibody in autoimmune disease, we investigated the effects of such a therapy in acute and chronic relapsing experimental allergic encephalomyelitis (EAE) by instituting treatment after the onset of paralytic signs and following the clinical course. In chronic relapsing EAE, animals treated with anti-I-As antibody had no mortality and fewer relapses when compared with control animals. Antibody levels to myelin basic protein were lower and histopathology showed milder lesions in the treated group. Similarly, in the acute EAE model, animals treated with anti-I-As antibody showed a dramatic reversal of paralytic signs and a rapid recovery. The mechanisms of action of antibody to IR gene products in autoimmune disease are discussed.

scholarly journals A T Helper Cell 2 (Th2) Immune Response against Non-self Antigens Modifies the Cytokine Profile of Autoimmune T Cells and Protects against Experimental Allergic Encephalomyelitis

1997 ◽  
Vol 185 (5) ◽  
pp. 901-908 ◽  
Author(s):  
Marika Falcone ◽  
Barry R. Bloom
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Profile ◽  
T Helper Cell ◽  
Th2 Cells ◽  
T Helper ◽  
Allergic Encephalomyelitis ◽  
Autoreactive T Cell ◽  
Cell Clones ◽  
Experimental Allergic

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS), and the most commonly used experimental model for multiple sclerosis. It is mediated by autoreactive T cell clones exhibiting a T helper cell (Th) 1 cytokine profile. Nonencephalitogenic T lymphocytes specific for self or exogenous antigens have been found to suppress encephalitogenic T cell responses and to protect against autoimmune disease. The mechanisms by which exogenous antigens modulate autoimmunity are not fully understood. In this study, we tested the hypothesis that a Th2-type immune response against an exogenous, nonself antigen, keyhole limpet hemocyanin (KLH), by releasing IL-4 in the microenvironment, could shift the cytokine profile of encephalitogenic T cells from an inflammatory Th1 to a protective Th2 type. SJL/J mice were preimmunized with the KLH in incomplete Freund's adjuvant to induce a population of Th2 memory cells that would be expected to release Th2 cytokines when activated by the specific antigen at the time of EAE induction. Four weeks later, mice received an encephalitogenic challenge containing guinea pig myelin in complete Freund's adjuvant with or without KLH. All KLH primed animals not receiving the exogenous antigen at the time of EAE induction developed a severe clinical disease indistinguishable from control mice not KLH primed. In contrast, animals preimmunized and challenged with the encephalitogenic inoculum containing KLH showed either no, or markedly reduced, clinical signs. Enzyme-linked immunospot analysis demonstrated that KLH-specific T cells in the primed mice were producing IL-4 characteristic of Th2 cells. In the KLH-primed and restimulated mice, the cytokine profile of the autoreactive, myelin basic protein–specific T cells was shifted from an inflammatory Th1 towards a protective Th2 type. We infer that the presence of IL-4 secreted by KLH-specific memory Th2 cells in the lymphoid system microenvironment in which the autoreactive T cells were engaged by the encephalitogenic stimulus were able to bias their cytokine profile towards a protective Th2 phenotype. This interpretation is supported by the observation that the protective effect of preimmunization with KLH was overcome by rm– IL-12, which inhibited the production of IL-4 by the Th1 cells and biased the autoimmune response to a predominantly Th1 type. Since IL-4 mRNA could not be detected by reverse transcriptase PCR in the CNS, the protective effect was inferred to be mediated by Th2 cells in the lymphoid system, and not the target organ. We conclude that exogenous, nonself antigens that can induce Th2 responses, can modify the cytokine environment sufficiently to alter the cytokine phenotype of inflammatory, autoreactive T cell clones, and ultimately, to provide significant protection against EAE and possibly other T cell–mediated autoimmune diseases.

scholarly journals Prevention and treatment of murine experimental allergic encephalomyelitis with T cell receptor V beta-specific antibodies.

1990 ◽  
Vol 171 (6) ◽  
pp. 1943-1955 ◽  
Author(s):  
D M Zaller ◽  
G Osman ◽  
O Kanagawa ◽  
L Hood
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental Allergic Encephalomyelitis ◽  
T Cell Response ◽  
Allergic Encephalomyelitis ◽  
Antibody Treatment ◽  
Susceptible Animal ◽  
Specific Antibodies ◽  
Prevention And Treatment ◽  
Experimental Allergic

Experimental allergic encephalomyelitis (EAE) is a model system for T cell-mediated autoimmune disease. Symptoms of EAE are similar to those of multiple sclerosis (MS) in humans. EAE is induced in susceptible animal strains by immunization with myelin basic protein (MBP) and potent adjuvant. The major T cell response to MBP in B10.PL mice is directed towards an NH2-terminal epitope and involves T cells expressing either V beta 8.2 or V beta 13 gene segments. Animals treated with a TCR V beta 8-specific mAb have a reduced incidence of EAE. We report here that the in vivo administration of a combination of anti-V beta 8.2 and anti-V beta 13 mAbs results in a long-term elimination of T cells involved in the response to MBP. When given before MBP immunization, anti-TCR antibody treatment leads to nearly complete protection against EAE. Antibody treatment also results in a dramatic reversal of paralysis in diseased animals. Thus, treatment with a combination of V beta-specific antibodies is a very effective therapy for the prevention and treatment of EAE. It is hoped that the future characterization of TCR V gene usage in human autoimmune diseases may lead to similar strategies of immune intervention.

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