Abstract
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.
Highlights
Type 1 diabetes (T1D) is a multifactorial autoimmune disease that remains a major health challenge [1]
In order to enforce the development of type 1 diabetes (T1D) in YES mice, we introduced the hB7.1 gene under the control of the rat insulin gene promoter (RIP) using the LV-RIP-hB7.1 vector [17]
While less than 2% conventional RIP-hB7.1 transgenic mice developed diabetes by 8 months of age [30], spontaneous diabetes was commonly observed in transgenic mice that co-expressed RIP-hB7.1 and the human insulin gene b cells [12, 31]
Summary
Type 1 diabetes (T1D) is a multifactorial autoimmune disease that remains a major health challenge [1]. Immunological markers for the autoimmune response to b cells have shown limitations in predicting the development of type 1 diabetes in subjects with prediabetes, especially when a single autoantibody is detected [3]. Following their use in preclinical models of T1D, antigen and peptide-specific immunotherapies have been proposed as strategies with a low risk/benefit ratio in human. The use of an immunodominant proinsulin peptide has proven to be well-tolerated and to delay C-peptide decline in human [5] From both a diagnostic and a therapeutic standpoint, preclinical models of T1D have fallen short of translating into human
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