Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model.

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  • Additional Information
    • Source:
      Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Research Foundation]
    • Subject Terms:
      Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Benzylisoquinolines/*therapeutic use ; Diabetes Mellitus, Type 1/*drug therapy ; HLA-DR3 Antigen/*metabolism ; Islets of Langerhans/*immunology ; Polyendocrinopathies, Autoimmune/*drug therapy ; T-Lymphocytes/*immunology ; Thyroiditis, Autoimmune/*drug therapy; Animals ; Antigen Presentation ; Autoantigens/immunology ; Binding Sites/genetics ; Cells, Cultured ; Diabetes Mellitus, Type 1/immunology ; Disease Models, Animal ; Genetic Predisposition to Disease ; Glutamate Decarboxylase/immunology ; HLA-DR3 Antigen/genetics ; Humans ; Immunity, Humoral ; Immunization ; Iodide Peroxidase/immunology ; Iron-Binding Proteins/immunology ; Lymphocyte Activation ; Mice ; Mice, SCID ; Peptide Fragments/genetics ; Peptide Fragments/immunology ; Polyendocrinopathies, Autoimmune/immunology ; Thyroglobulin/genetics ; Thyroglobulin/immunology ; Thyroiditis, Autoimmune/immunology
    • Abstract:
      Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro . We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo . These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.
      Competing Interests: YT declares that he was previously (1/2015 – 6/2017) the principal investigator on a basic research project jointly funded by the Juvenile Diabetes Research Foundation and Pfizer. The current manuscript is not related to that research project. YT and CL declare that they submitted a patent application for Cepharanthine as a treatment for APS3v and T1D. YT, RO, and LF have additional patent applications that are not related to the content of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
      (Copyright © 2021 Li, Osman, Menconi, Faustino, Kim, Clarke, Hou and Tomer.)
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    • Grant Information:
      R01 DK067555 United States DK NIDDK NIH HHS; R01 DK073681 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: autoimmune polyglandular syndrome; autoimmune thyroiditis; cepharanthine; immune therapy; type 1 diabetes
    • Accession Number:
      0 (Anti-Inflammatory Agents, Non-Steroidal)
      0 (Autoantigens)
      0 (Benzylisoquinolines)
      0 (HLA-DR3 Antigen)
      0 (Iron-Binding Proteins)
      0 (Peptide Fragments)
      7592YJ0J6T (cepharanthine)
      9010-34-8 (Thyroglobulin)
      EC 1.11.1.7 (TPO protein, human)
      EC 1.11.1.8 (Iodide Peroxidase)
      EC 4.1.1.15 (Glutamate Decarboxylase)
    • Publication Date:
      Date Created: 20220106 Date Completed: 20220225 Latest Revision: 20220225
    • Publication Date:
      20221213
    • Accession Number:
      PMC8721038
    • Accession Number:
      10.3389/fimmu.2021.796552
    • Accession Number:
      34987519