title: Cytotoxic T-cells specific for natural IgE peptides downregulate IgE production.
abstract: Immunoglobulin E (IgE) plays a central role in IgE-mediated immediate type hypersensitivity. Since production of IgE depends on Th2, efforts to block IgE production and control allergic reactions include tolerization of Th2 or deviating development of Th2. We hypothesized that cytotoxic T lymphocytes targeting natural IgE peptides/MHC I complexes can eliminate IgE-producing cells and inhibit centrally IgE production. CTL to self-IgE peptides were elicited in mice immunized with nonameric p109-117, p113-121, and p103-141 (CHepsilon2 domain), which encompass both peptides with an OVA helper peptide (OVAp restricted for H-2d/b) in liposomes and presented by dendritic cells (DC). CTL from BALB/c lysed IgE peptide-pulsed P815 target as well as IgE-producing 26.82 hybridomas (H-2d). Natural tolerance to self-IgE peptides was tested in IgE sufficient (IgE +/+) as well as IgE-deficient (IgE -/-) 129/SvEv mice (H-2b). Comparable magnitude of CTL responses was observed in both strains immunized with p109-117 or p103-141 concomitantly with CD4 T-cell costimulation. CTL from 129/SvEv lysed not only IgE peptide-pulsed EL-4 but also IgE-producing B4 hybridomas (H-2b). This observation strongly suggests a correspondence of epitope of immunogenic peptide to that of physiologically processed IgE peptides presented on IgE-producing cells. Moreover, CTL were generated in 129/SvEv, immunized with the recombinant antigenized antibody in liposomes encompassing p107-123, p109-117, and p113-121 expressed in CDR3 of VH62/human gamma1. Polyclonal IgE production was inhibited by coincubation with MHC I-restricted CTL in vitro. Furthermore, antigen-specific IgE responses were inhibited in mice, immunized with p109-117 and p103-141 while IgG responses were not suppressed. Since IgE peptide sequences of CHepsilon2 are ubiquitous to all murine IgE heavy chain, peptides made as such can serve as a universal IgE vaccine to prevent allergy for a myriad of allergens in rodents. This observation suggests that similar human IgE peptides should be identified and employed to downregulate human IgE production.
authors.affiliation: Department of Allergy and Immunology, The Institute of Genetics, 6740 Nancy Ridge Drive, San Diego, CA 92121, USA. achen@i-genetics.org
authors.forename: Swey-Shen
authors.initials: SS
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Gong
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Yang
authors.forename: Hans
authors.initials: H
authors.lastname: Oettgen
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D022801:Complementarity Determining Regions / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D006433:Hemocyanins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006825:Hybridomas / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy; D007114:Immunization; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology*; D016233:Immunotherapy, Active / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000906:Antibodies; D022801:Complementarity Determining Regions; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; C111390:OVA 323-339; D010446:Peptide Fragments; D011994:Recombinant Proteins; D023201:CD40 Ligand; D007073:Immunoglobulin E; D010047:Ovalbumin; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin