title: Peptide-based immunotherapy of experimental autoimmune encephalomyelitis without anaphylaxis.
abstract: Administration of peptide antigens in tolerogenic form holds promise as a specific treatment for autoimmune and allergic disorders. However, experiments in rodent autoimmune models have highlighted the risk of anaphylaxis in response to systemic peptide application once the aberrant immune response is underway. Thus, mice with clinical signs of experimental autoimmune encephalomyelitis (EAE) or diabetes have been reported to suffer fatal anaphylaxis upon administration of native autoantigenic peptides. Clearly, this might represent a significant barrier to the use of synthetic peptides in the treatment of ongoing human autoimmune conditions. Here we describe the development of an altered peptide ligand (APL) engineered to prevent anaphylaxis (no antibody binding) whilst retaining the ability to silence pathogenic myelin-reactive T lymphocytes. Administration of the APL to mice with an ongoing anti-myelin immune response did not cause anaphylaxis, but led to complete protection from the subsequent induction of EAE and, when given during ongoing EAE, led to a rapid remission of clinical signs. The approach of removing antibody recognition whilst maintaining the desired functional effect (in this case T cell tolerance) may be of value in other situations in which there is a risk of triggering anaphylaxis with peptide-based drugs.
authors.affiliation: University of Edinburgh, Institute of Immunology and Infection Research, School of Biological Sciences, Edinburgh, UK.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Leech
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Chung
authors.forename: Abigail
authors.initials: A
authors.lastname: Culshaw
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
mesh_terms: D000707:Anaphylaxis / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D001665:Binding Sites; D003888:Desensitization, Immunologic / Q000009:adverse effects / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D007108:Immune Tolerance; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D007074:Immunoglobulin G; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C526792:myelin oligodendrocyte glycoprotein (35-50), Ala(37)-; C445081:myelin oligodendrocyte glycoprotein (35-55)