A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

Front Immunol. 2021 Oct 14;12:748679. doi: 10.3389/fimmu.2021.748679. eCollection 2021.


To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4+ and CD8+ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease.

Keywords: HLA-DQ8; autoimmunity; epitopes; humanized mouse; preproinsulin; type 1 diabetes (T1D).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • B7-1 Antigen / genetics*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cytotoxicity, Immunologic
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Models, Animal
  • Female
  • H-2 Antigens / genetics
  • HLA-A2 Antigen / genetics
  • HLA-DQ Antigens / genetics*
  • Humans
  • Insulin / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Young Adult


  • B7-1 Antigen
  • H-2 Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Insulin