Multiple sclerosis is an autoimmune disease of the central nervous system in which T cell reactivity to several myelin proteins, including myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG), has been implicated in the perpetuation of the disease state. Experimental autoimmune encephalomyelitis (EAE) is used commonly as a model in which potential therapies for multiple sclerosis are evaluated. The ability of T cell epitope-containing peptides to down-regulate the disease course is well documented for both MBP- and proteolipid protein-induced EAE, and recently has been shown for MOG-induced EAE. In this study, we describe a novel EAE model, in which development of severe disease symptoms in (PL/J x SJL)F1 mice is dependent on reactivity to two different immunizing Ags, MBP and MOG. The disease is often fatal, with a relapsing/progressive course in survivors, and is more severe than would be predicted by immunization with either Ag alone. The MOG plus MBP disease can be treated postinduction with a combination of the MOG 41-60 peptide (identified as the major therapeutic MOG epitope for this strain) and the MBP Ac1-11[4Y] peptide. A significant treatment effect can also be obtained by administration of the MBP peptide alone, but this effect is strictly dose dependent. This MBP peptide does not treat the disease induced only with MOG. These results suggest that peptide immunotherapy can provide an effective means of mitigating disease in this model, even when the treatment is targeted to only one component epitope or one component protein Ag of a diverse autoimmune response.

Experimental autoimmune encephalomyelitis (EAE) serves as a rodent model of the autoimmune disease multiple sclerosis. In mice, EAE is induced by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PLP), or peptides derived from these components. EAE can be induced in H-2u or (H-2u × H-2s)F1 mice with the N-terminal peptide of MBP, Ac1-11. Coimmunization with Ac1-11 and Ac1-11[4A], an analog in which lysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of encephalitogenic T cells. We have isolated T cell clones and hybridomas from (PL/JXSJL/J)F1 mice immunized with either Ac1-11 alone or Ac1-11 and Ac1-11[4A] and analysed these cells for differences in their T cell receptor repertoire andin vitro response. Although T cells elicited by coinjection of Ac1-11 and Ac1-11[4A] expressed TCR that used Vα and Vβ gene elements similar to those elicited by Ac1-11 alone, they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Ac1-11in vitro, suggesting that coinjection of Ac1-11 and Ac1-11[4A] preferentially activates T cells bearing TCR of different affinity for Ac1-11 bound to I-Au, and which may therefore be less encephalitogenic. Furthermore, our results show that a more diverse repertoire of Vα and Vβ genes are elicited by Ac1-11 in (PL/JXSJL/J)F1 mice compared to PL/J and B10.PL mice, providing further evidence that a restricted TCR repertoire is not required for the development of autoimmune disease.

Myelin oligodendrocyte glycoprotein (MOG) is a transmembrane glycoprotein expressed on the surface of central nervous system (CNS) myelin membranes, which has been shown to induce experimental autoimmune encephalomyelitis (EAE) in rodents. Here we describe the induction of EAE in SJL and (PLJ X SJL)F1 mice with truncated human recombinant MOG (thr-MOG, amino acids 1-120) which has been expressed in insect cells in soluble form. We show that in SJL mice, immunization with thr-MOG produces an immune response to the 1-30 and the 81-110 regions of the MOG molecule. We also demonstrate effective treatment of thr-MOG-induced EAE in SJL mice with intravenous injections of a single peptide, MOG 91-110. These results support the possibility of treating MS using an antigen dependent approach.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease induced by immunization with myelin basic protein (MBP), proteolipid protein, or encephalitogenic peptides from these myelin components. EAE resembles basic protein multiple sclerosis in some of its clinical and histologic features, and serves as an experimental model for this and other autoimmune diseases. In this study, we examine i.v. peptide therapy of EAE in detail, and show that repeated i.v. injections of MBP peptides effectively treat EAE in (PLJxSJL)F1 mice. In this study, administration of the immunodominant epitope (MBP Ac1-11) prevents MBP-induced disease, whereas the subdominant epitope MBP 31-47 is neither required nor sufficient. Intravenous administration of substituted MBP peptide analogues is also effective in treating EAE, provided the peptide side chains presumed to be involved in TCR contact and MHC binding are preserved. A substituted MBP peptide analogue that forms long-lived peptide-MHC complexes in vivo is more effective than the unmodified MBP peptide. Lower doses of the substituted peptide analogue are effective, and the effect is longer lasting than treatment with the unmodified peptide. Clinical signs of EAE are reversed by injection of the substituted peptide during the acute phase of disease. Moreover, treatment of mice in the remission phase of EAE results in a dramatically reduced incidence of relapse. In summary, we have shown that EAE can be reversed after onset and treated during remission with an MBP peptide analogue that has been modified for improved therapeutic potency.

The precise mechanisms of failure of immunological tolerance to self proteins are not known. Major histocompatibility complex (MHC) susceptibility alleles, the target peptides, and T cells with anti-self reactivity must be present to cause autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a murine model of a human autoimmune disease, multiple sclerosis. In EAE, residues 1-11 of myelin basic protein (MBP) are the dominant disease-inducing determinants in PL/J and (PL/J x SJL/J)F1 mice. Here we report that a six-residue peptide (five of them native) of MBP can induce EAE. Using peptide analogues of the MBP-(1-11) peptide, we demonstrate that only four native MBP residues are required to stimulate MBP-specific T cells. Therefore, this study demonstrates lower minimum structural requirements for effective antigen presentation by MHC class II molecules. Many viral and bacterial proteins share short runs of amino acid similarity with host self proteins, a phenomenon known as molecular mimicry. Since a six-residue peptide can sensitize MBP-specific T cells to cause EAE, these results define a minimum sequence identity for molecular mimicry in autoimmunity.

Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1–11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin- 5 gene.

The minimum structural requirements for peptide interactions with major histocompatibility complex (MHC) class II molecules and with T cell receptors (TCRs) were examined. In this report we show that substituting alanines at all but five amino acids in the myelin basic protein (MBP) peptide Ac1-11 does not alter its ability to bind A-alpha(u)A-beta(u) (MHC class II molecules), to stimulate specific T cells and, surprisingly, to induce experimental autoimmune encephalomyelitis (EAE) in (PL/J x SJL/J)F1 mice. Most other amino acid side chains in the Ac1-11 peptide are essentially irrelevant for T cell stimulation and for disease induction. Further analysis revealed that binding to A-alpha(u)A-beta(u) occurred with a peptide that consists mainly of alanines and only three of the original residues of Ac1-11. Moreover, when used as a coimmunogen with MBP Ac1-11, this peptide inhibited EAE. The finding that a specific in vivo response can be generated by a peptide containing only five native residues provides evidence that disease-inducing TCRs recognize only a very short sequence of the MHC-bound peptide.

The cellular and molecular requirements for the autoimmune disease EAE are being defined in increasing detail through intense scrutiny of critical autoantigenic peptides, class II MHC molecules, and alpha beta TCRs involved in the disease process. This study has led to novel immunotherapeutic approaches, many of which are based on the administration of synthetic peptides. Since short peptides are understood to be the minimal antigenic units bound by MHC molecules for recognition by T cells, they are attractive experimental tools for finely modulating specific immune responses. It is clear that a large number of defined peptides can dramatically influence the course of EAE. Table IV lists a number of potential mechanisms which may mediate disease prevention. Increasing evidence supports the idea that prevention of autoimmune disease can result from MHC-blockade by peptides which competitively bind to class II molecules. However, for some peptides such as the perplexing partial agonist Ac1-11[4A], the mechanism by which these precisely defined units act is not yet fully understood. Numerous hurdles hinder immediate clinical application of peptide-based immunotherapy. Nevertheless, the knowledge gained by probing experimental autoimmunity with defined peptides promises to inspire original and practical approaches to treating human autoimmune disease.

It is now well accepted that T helper cells play a central role in the induction and maintenance of autoimmune disease. Many experimental models have emphasized this fact and have illustrated the efficacy of therapeutic strategies aimed at disrupting T cell recognition of autoantigens. Antibodies directed at either class II proteins of the major histocompatibility complex (MHC) or CD4 accessory molecules have been universally successful. However, the potential use of antibodies for therapy in humans is complicated by host anti-globulin and anti-idiotype responses. An alternative approach to anti-MHC blockade with antibodies is peptide blockade of MHC molecules. In addition, peptides may be used as agonists of autoantigens in order to modulate the autoimmune response. The use of synthetic peptides for therapy is an innovative yet relatively unexplored approach and will be the subject for discussion in this article.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory neurologic disease initiated by myelin basic protein-reactive CD4+ T cells, which are restricted by a particular MHC class II molecule. Recent studies have utilized inhibitor peptides that bind to restricting MHC class II molecules in order to inhibit EAE, presumably by means of competing with encephalitogenic epitopes. However, these studies leave open the possibility of alternative explanations, such as Ag-specific nonresponsiveness and immunodominance. In order to demonstrate that competition for MHC binding alone can inhibit EAE, the inhibitor peptide should ideally be structurally unrelated and nonimmunogenic yet physically associate with the MHC class II molecule. In this study, we show that the OVA-323-339 peptide, which is unrelated to the disease-inducing peptide, binds to A alpha uA beta u. However, although OVA-323-339 is extremely immunogenic in A alpha dA beta d-expressing BALB/c mice, it is nonimmunogenic in (PL/J x SJL)F1 and PL/J mice expressing A alpha uA beta u. When administered as a coimmunogen with Ac1-11, OVA-323-339 inhibited induction of EAE in (PL/J x SJL)F1 mice. Myelin basic protein-89-101, which does not bind A alpha uA beta u, had no effect on the disease process. This study provides evidence that MHC class II binding alone can modulate the induction of EAE. The use of a nonimmunogenic non-self peptide to modulate an autoimmune disease minimizes the potential complications of immunodominance or alternative regulatory mechanisms associated with immunogenic peptide therapies and further confirms the MHC-blocking model of immunosuppression.

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.

Peptide binding and lymph node T cell activation studies have been used to characterize T cell recognition of an encephalitogenic T cell autoantigen from myelin basic protein in mice of the H-2u haplotype. An important role for MHC class II molecules in "determinant selection" is revealed. Amino acids which determine interactions with either the restriction element of the major histocompatibility complex (MHC) or the encephalitogenic T cell receptor are defined. This information enables the design of peptides which bind MHC yet do not crossreact with the autoantigen. Two such peptides compete with the autoantigen for binding to the disease associated class II molecule and inhibit induction of experimental autoimmune encephalomyelitis in H-2u mice. Prospects for peptide mediated therapy are discussed.

Immunological ReviewsVolume 118, Issue 1 p. 37-71 Antigen Recognition and Peptide-Mediated Immunotherapy in Autoimmune Disease Dawn E. Smilek, Dawn E. Smilek Department of Microbiology & ImmunologySearch for more papers by this authorChristopher B. Lock, Christopher B. Lock Department of Microbiology & ImmunologySearch for more papers by this authorHugh O. Mcdevitt, Hugh O. Mcdevitt Departments of Microbiology & Immunology, and of Medicine, Stanford University School of Medicine, Stanford, CA 94305, U.S.A.Search for more papers by this author Dawn E. Smilek, Dawn E. Smilek Department of Microbiology & ImmunologySearch for more papers by this authorChristopher B. Lock, Christopher B. Lock Department of Microbiology & ImmunologySearch for more papers by this authorHugh O. Mcdevitt, Hugh O. Mcdevitt Departments of Microbiology & Immunology, and of Medicine, Stanford University School of Medicine, Stanford, CA 94305, U.S.A.Search for more papers by this author First published: December 1990 https://doi.org/10.1111/j.1600-065X.1990.tb00813.xCitations: 19Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume118, Issue1December 1990Pages 37-71 RelatedInformation

Peptide binding and lymph node T cell activation studies have been used to characterize T cell recognition of an encephalitogenic T cell autoantigen from myelin basic protein in (PLJ × SJL)F1 mice. Amino acids that determine interactions with either the restriction element of the major histocompatibility complex (MHC) or the encephalitogenic T cell receptor are defined. This information enables the design of peptides that bind MHC yet do not cross-react with the autoantigen. A peptide analog of the encephalitogenic epitope is shown to be “heteroclitic” for MHC binding and activation of encephalitogenic T cells in vitro. This analog is not immunogenic for encephalitogenic T cells in vivo and is shown to inhibit disease that is induced by the autoantigen itself.

Initiation of the immune response to foreign protein antigens and, presumably, to self-protein antigens in the case of autoimmunity is the result of an initial interaction with a peptide fragment of the protein antigen and a major histocompatibility complex (MHC) class II molecule. Following binding of a degraded peptide fragment of the protein in the active binding site of the class II molecule, recognition of this complex by T cells with complementary T-cell receptors initiates the development of memory helper T cells and triggers the proliferation of both T-cell and B-cell immune responses to the degraded fragments of the antigen and to the intact three-dimensional protein (Moller 1987).

Sixteen Lewis anti-Brown Norway monoclonal antibodies and sera from alloimmunized Lewis rats were used to study the topographic relationships of antigenic determinants on class I major histocompatibility gene products. Only two independent antigenic regions were identified in competition binding assays. The first region is composed of a set of overlapping epitopes that are conserved in class I major histocompatibility products of mice and humans, as well as rats. In contrast, the second antigenic region appears in a restricted number of inbred rat strains and is not detected in other species. The data provide serologic confirmation, at the monoclonal and serum alloantibody level, of conserved polymorphisms in the major histocompatibility gene products of different species, a finding that is consistent with the amino acid sequences of these molecules.

24 monoclonal rat antibodies are described that are reactive with determinants encoded by the major histocompatibility complex (MHC) of the rat. These hybridoma antibodies were derived by fusing mutant mouse myeloma cells to spleen cells from Lewis rats immunized with allogeneic Brown Norway cells. All 24 antibodies are cytotoxic for both Brown Norway target cells and target cells from the appropriate MHC congenic rats. Pattern of cytotoxicity and hemagglutination strongly suggest reactivity against class I (K or D equivalent) rat MHC determinants. Cytotoxic cross-reactivity patterns were generated for each monoclonal antibody on a panel of rat and mouse lymphoid cells and human peripheral T lymphocytes. A high degree of interspecies cross-reactivity was noted with approximately one-half of the antibodies positive on human and/or mouse target cells. 11 antibodies recognized polymorphic determinants in the mouse, and, by using target cells from MHC congenic mouse strains, it was shown that these determinants are encoded by genes within the H-2 complex. Finally, by considering the overall reactivity patterns of these monclonal antibodies on all target cells, one can show that these 24 antibodies represent a minimum of 14 antibody specificities.

Immunological ReviewsVolume 47, Issue 1 p. 91-115 Properties of Rat Anti-MHC Antibodies Produced by Cloned Rat-Mouse Hybridomas Thomas J. McKearn, Thomas J. McKearn The Department of Pathology, Division of Research Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 U.S.A.Search for more papers by this authorFrank W. Fitch, Frank W. Fitch The Committee on Immunology and The Department of Pathology, University of Chicago, Chicago, Illinois 60637 U.S.A.Search for more papers by this authorDawn E. Smilek, Dawn E. Smilek The Department of Pathology, Division of Research Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 U.S.A.Search for more papers by this authorMarion Sarmiento, Marion Sarmiento The Committee on Immunology and The Department of Pathology, University of Chicago, Chicago, Illinois 60637 U.S.A. Postdoctoral fellow of the Pathobiology Training Program, U.S. Public Health Service Training Grant GM-07i90.Search for more papers by this authorFrank P. Stuart, Frank P. Stuart The committee on Immunology and The Department of Surgery, University of Chicago, Chicago, Illinois 60637 U.S.A.Search for more papers by this author Thomas J. McKearn, Thomas J. McKearn The Department of Pathology, Division of Research Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 U.S.A.Search for more papers by this authorFrank W. Fitch, Frank W. Fitch The Committee on Immunology and The Department of Pathology, University of Chicago, Chicago, Illinois 60637 U.S.A.Search for more papers by this authorDawn E. Smilek, Dawn E. Smilek The Department of Pathology, Division of Research Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 U.S.A.Search for more papers by this authorMarion Sarmiento, Marion Sarmiento The Committee on Immunology and The Department of Pathology, University of Chicago, Chicago, Illinois 60637 U.S.A. Postdoctoral fellow of the Pathobiology Training Program, U.S. Public Health Service Training Grant GM-07i90.Search for more papers by this authorFrank P. Stuart, Frank P. Stuart The committee on Immunology and The Department of Surgery, University of Chicago, Chicago, Illinois 60637 U.S.A.Search for more papers by this author First published: October 1979 https://doi.org/10.1111/j.1600-065X.1979.tb00290.xCitations: 53AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES Bach, E. H., Grillot-Courvalin, C., Kuperman, O. J., Sollinger, H. W., Hayes, C., Sondel, P. M., Alter, B. J. & Bach, M.L. (1977) Antigenic requirements for triggering of cytotoxic T lymphocytes. Immunol. Rev. 35, 76. 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