Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes

Falk, Kirsten; Rötzschke, Olaf; Santambrogio, Laura; Dorf, Martin E.; Brosnan, Celia F.; Strominger, Jack L.

doi:10.1084/jem.191.4.717

Cited by 45 publications

(22 citation statements)

References 44 publications

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“…Two different neuritogenic, P2 53-78 -specific T cell lines (G7 and the clone TKtsA6) were challenged with titrated amounts of antigen. As previously shown in other systems, the 16-mer was significantly more potent than the 4-mer (4,17). However, in contrast to the previous report (4) the proliferative response toward P2-16-mer, at least with the T cells tested, was in most cell lines weaker than the response triggered by the monomeric peptide.…”

Section: Resultssupporting

confidence: 47%

“…T cell epitope oligomers of this type have been shown to be particularly effective in the specific suppression of experimental autoimmune encephalomyelitis (EAE) by the induction of ''high zone tolerance'' (16,17). In contrast to other broadly immunosuppressive mechanisms, this new therapeutic approach for prevention and therapy of autoimmune diseases aimed more specifically at the antigen-specific elimination of autoreactive T cells.…”

Section: Imerization or Oligomerization Of T Cell Receptor (Tcr)mentioning

confidence: 99%

“…The therapeutic effect of P2-16-mer on the development of clinical signs of EAN was studied by employing a protocol previously used for the treatment of EAE (17). Female Lewis rats were injected intravenously with P2-16-mer on days 8 and 12 after active induction of disease with the neuritogenic P2 peptide (P2 53-78 )-i.e., shortly before and at the onset of EAN.…”

Section: Prevention Of Ean By the P2-16-mermentioning

confidence: 99%

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Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Stienekemeier

Falk

Rötzschke

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultssupporting

confidence: 47%

Section: Imerization or Oligomerization Of T Cell Receptor (Tcr)mentioning

confidence: 99%

Section: Prevention Of Ean By the P2-16-mermentioning

confidence: 99%

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Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Stienekemeier

Falk

Rötzschke

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Two protocols that have shown promise in inducing antigen-specific immune tolerance for the prevention and͞or treatment of EAE are the i.v. injection of soluble protein, peptide, or peptide oligomers (8)(9)(10) and the i.v. injection of myelin proteins or peptides chemically coupled to syngeneic splenocytes [antigen-coupled splenocytes (Ag-SP)] (11).…”

mentioning

confidence: 99%

Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis

Smith

Eagar

Strominger

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The ability of different forms of myelin peptides to induce tolerance for the treatment of preestablished murine experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, was evaluated. i.v. administration of myelin peptidepulsed, ethylene carbodiimide-fixed syngeneic splenocytes, but not soluble myelin peptide monomers or oligomers, proved exceedingly effective at treating preestablished EAE, resulting in amelioration of disease progression. In addition to the lack of therapeutic efficacy of soluble peptide and peptide oligomer, administering them i.v. after the onset of clinical symptoms in many but not all peptide-induced EAE models led to a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and, often, death. By using anti-IgE antibody treatments and mice with targeted mutations of the Fc␥RIII ␣-chain or the common ␥-chain of Fc RI and Fc␥RI͞III, we demonstrate that IgE crosslinking of Fc RI appears to be necessary and sufficient for myelin peptide-induced anaphylaxis. The implications of these findings to myelin peptide͞ protein tolerance strategies for the treatment of multiple sclerosis are discussed.myelin ͉ tolerance M ultiple sclerosis (MS) is a CNS-demyelinating disease characterized by the perivascular infiltration of inflammatory mononuclear cells (1). Although the etiology of MS is unknown, evidence from human patients (2-4) and an animal model of MS, experimental autoimmune encephalomyelitis (EAE) (5-7), supports a major pathogenic role for autoreactive myelin-specific CD4 ϩ T cells, which are a logical target for clinical therapies. Two protocols that have shown promise in inducing antigen-specific immune tolerance for the prevention and͞or treatment of EAE are the i.v. injection of soluble protein, peptide, or peptide oligomers (8-10) and the i.v. injection of myelin proteins or peptides chemically coupled to syngeneic splenocytes [antigen-coupled splenocytes (Ag-SP)] (11). We performed a side-by-side comparison of these two tolerance protocols in preventing EAE induction and ameliorating ongoing EAE. We found that i.v. injection of soluble peptide monomer was not particularly effective when administered at any time point tested, and a soluble peptide oligomer was only fully effective when administered after immunization (day ϩ7) but before the onset of clinical symptoms of EAE. In contrast, i.v. administration of Ag-SP proved effective at preventing the onset of clinical symptoms and treating preestablished disease. In addition, an unexpected result of the administration of soluble peptide and peptide oligomer after the onset of clinical symptoms in many, but not all, peptide-induced EAE models was a rapid-onset anaphylactic reaction characterized by respiratory distress, erythema, decreased body temperature, unresponsiveness, and often death. This result is especially alarming given the proposed use of peptide-based tolerance therapies for the treatment of autoimmune diseases.Anaphylaxis i...

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“…Oligomerization of T helper epitopes has been proven to be very potent in enhancing the immunogenicity as well as the tolerance-inducing capacity of antigenic epitopes in vivo (21). How the Ii proteins described here compare in efficacy with oligomerized T cell epitopes remains to be established.…”

Section: Discussionmentioning

confidence: 99%

Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes

Bischof

Wienhold

Wirblich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The invariant chain (Ii) binds to newly synthesized MHC class II molecules with the CLIP region of Ii occupying the peptide-binding groove. Here we demonstrate that recombinant Ii proteins with the CLIP region replaced by antigenic self-epitopes are highly efficient in activating and silencing specific T cells in vitro and in vivo. The Ii proteins require endogenous processing by antigenpresenting cells for efficient T cell activation. An Ii protein encompassing the epitope myelin basic protein amino acids 84 -96 (Ii-MBP84 -96) induced the model autoimmune disease experimental allergic encephalomyelitis (EAE) with a higher severity and earlier onset than the peptide. When applied in a tolerogenic manner, Ii-MBP84 -96 abolished antigen-specific T cell proliferation and suppressed peptide-induced EAE more effectively than peptide alone. Importantly, i.v. administration of Ii proteins after EAE induction completely abrogated the disease, whereas peptides only marginally suppressed disease symptoms. Ii fusion proteins are thus more efficient than peptide in modulating CD4 ؉ T cellmediated autoimmunity, documenting their superior qualities for therapeutic antigen delivery in vivo. C D4 ϩ T cells recognize peptides presented in association withMHC class II molecules on the surface of antigen-presenting cells. Peptide loading of MHC class II molecules is regulated by the chaperone molecule invariant chain (Ii). Trimers of Ii form nonameric complexes with newly synthesized MHC class II ␣␤-heterodimers within the endoplasmic reticulum. In these complexes, the CLIP core region (amino acids 90-98 in mice) of Ii occupies the peptide-binding groove of the class II molecule irrespective of the MHC haplotype (1, 2). In addition, sequences on both sides of the CLIP core region bind to the class II molecule (3-5).Genetically modified Ii proteins, in which the CLIP core region has been replaced by a T helper epitope, can be processed and presented in vitro to T cell clones by HLA DR-expressing cell lines (6, 7). Here we show that such genetically modified Ii proteins are superior to the peptide epitopes in triggering polyclonal, antigen-specific T cell populations in vitro and in vivo and, most importantly, in modulating autoimmunity in vivo. Our model system uses the peptides MBP84-96 and PLP139-151, immunodominant epitopes of the self-antigens myelin basic protein (MBP) and myelin proteolipid protein (PLP). MBP84-96 and PLP139-151 induce experimental allergic encephalomyelitis (EAE), a CD4 ϩ T cell-mediated experimental autoimmune disease, in immunized SJL mice (8, 9). We show that Ii proteins, wherein the CLIP core region has been replaced by MBP84-96 or PLP139-151, are more potent than the peptides in activating specific T cells in vitro and in vivo. Ii-MBP84-96, but not the peptide, required endogenous antigen processing by antigen-presenting cells to stimulate MBP84-96-specific T cells. Lower amounts of the Ii proteins were sufficient to break self-tolerance and induce autoimmunity in mice. On the other hand, i.p. injection...

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Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes

Cited by 45 publications

References 44 publications

Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope

Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis

Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes

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