title: A novel peptide mimotope identified as a potential immunosuppressive vaccine for organ transplantation.
abstract: We reported that anti-histone H1 autoantibody is one of the main immunosuppressive factors in serum that is induced after orthotopic liver transplantation in a rat tolerogenic model. We generated a novel anti-histone H1 IgM mAb produced by hybridoma 16G9 (16G9 mAb) that shows MLR-inhibitory activity. Identification of a functional epitope responsible for the immunosuppressive activity of 16G9 mAb may lead to the establishment of a novel therapeutic strategy. We used a combinatorial phage display peptide library to screen for peptides that bind to 16G9 mAb. Consequently, two peptides that bind to 16G9 mAb, SSV and LPQ, were selected from the library. The binding of 16G9 mAb to histone H1 was inhibited by SSV. SSV was recognized by rat tolerogenic post-orthotopic liver transplantation serum and the binding to SSV was inhibited by histone H1. Mice were immunized with keyhole limpet hemocyanin-conjugated SSV and LPQ. Abs induced by SSV immunization inhibited Con A-stimulated splenocyte proliferation, and the inhibition was neutralized by preincubation with SSV. Splenocytes stimulated by anti-CD3 Ab were inhibited by SSV-induced Abs using CFSE labeling. SSV immunization in rats before heterotopic heart transplantation resulted in significant prolonged allograft survival. These findings suggested that SSV is a functional histone H1-binding epitope for 16G9 mAb. SSV is capable of determining serum immunoreactivity against histone H1 as an index marker for tolerance. The inhibitory activity of SSV-induced Abs on blast cell proliferation and the prolonged graft survival that results from SSV immunization imply a potential for the development of an immunosuppressive vaccine.
authors.affiliation: Kazusa Institute for Drug Discovery, Josai International University, Kisarazu, Chiba, Japan.
authors.forename: Kuei-Chen
authors.initials: KC
authors.lastname: Chiang
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Shimada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Lai
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Hsu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Goto
authors.forename: Naoya
authors.initials: N
authors.lastname: Ohmori
authors.forename: Kenji
authors.initials: K
authors.lastname: Mori
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Miyagi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawamoto
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Ono
authors.forename: Chao-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Takeshi
authors.initials: T
authors.lastname: Goto
authors.forename: Shuji
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D019151:Peptide Library; D010455:Peptides; D051381:Rats; D011917:Rats, Inbred Lew; D014612:Vaccines / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D006657:Histones; D007166:Immunosuppressive Agents; D019151:Peptide Library; D010455:Peptides; D014612:Vaccines