Oral Administration of Recombinant Live Yeast Producing Altered Peptide Ligand Derived from Insulin B:9-23 Peptide Linked to Cholera Toxin B Subunit Suppresses Development of Autoimmune Diabetes in NOD Mice

DOI IR IR (HANDLE)
  • ZHOU Hongbo
    Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences
  • ABIRU Norio
    Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences
  • ARAKAWA Takeshi
    Molecular Microbiology Group, Tropical Biosphere Research Center, University of the Ryukyus
  • SAKIMA Rina
    Department of Parasitology, Graduate School of Medicine, University of the Ryukyus
  • MIYATA Takeshi
    Molecular Microbiology Group, Tropical Biosphere Research Center, University of the Ryukyus
  • KOBAYASHI Masakazu
    Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences
  • FUKUSHIMA Keiko
    Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences
  • KAWASAKI Eiji
    Metabolism⁄Diabetes and Clinical Nutrition, Nagasaki University Hospital
  • YAMASAKI Hironori
    Health Center, Nagasaki University
  • EGUCHI Katsumi
    Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences

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Insulin is a major autoantigen responsible for the pathogenesis of type 1 diabetes, and its B-chain peptide B:9-23 has been suggested to contain critically important epitopes in the NOD mouse. We have previously demonstrated that the altered peptide ligand of B:9-23 peptide with alanine substitutions at positions 16 and 19 (A16,19APL) suppresses insulitis and reduces the incidence of diabetes when administered intranasally together with cholera toxin (CT). In this study, we extended the previous findings to determine whether mucosal administration of the A16,19APL without the use of toxic CT is efficacious for diabetes prevention. To this end, we linked the A16,19APL to the C-terminus of non-toxic cholera toxin (CTB) B subunit and the chimeric fusion protein was produced in methyloprophic yeast Pichia pastoris. Although intranasal administration of the recombinant CTB-A16,19APL fusion protein extracted from the yeast cells failed to prevent the progression to diabetes, oral administration of the live yeast cells producing the chimeric protein resulted in more than 50% reduction of the development of diabetes, albeit the fact that protective efficacy did not reach the significance level by life table analysis (P = 0.08). Furthermore, the expression of insulin autoantibodies was not altered throughout the course of oral immunization experiment. These results demonstrated that the efficacy of recombinant CTB-A16,19APL for oral immunization has much room for improvement. Nevertheless, oral administration of recombinant yeast or other edible materials such as food plants engineered to produce altered autoantigenic peptide could potentially become a novel non-invasive immunotherapeutic strategy for type 1 diabetes. (250 word)

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