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A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

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.

SUBMITTER: Luce S

PROVIDER: S-EPMC8551915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A humanized mouse strain that develops spontaneously immune-mediated diabetes.

Project description:The clinical management of type 1 diabetes (T1D) faces the lack of fully predictive biomarkers and of antigen-specific therapies to prevent its development. From a therapeutic standpoint, preclinical modls of T1D have fallen short of directly translating into the human. To circumvent this limitation, we developed a new mouse model that is deficient for expression of murine major histocompatibility complex class I, class II and of murine insulin genes and instead expresses HLA-A*02:01, the high susceptibility HLA-DQ8 molecule and human insulin. The metabolic and immune phenotype of these mice is basically identical to that of the parental strains. Upon expression of B7.1 under the control of the rat insulin promoter, these mice develop T1D along with a T-lymphocyte response to human preproinsulin epitopes spanning the whole autoantigen sequence. This new model will allow evaluating peptide-based immunotherapy that may directly apply to human T1D.

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A humanized mouse strain that develops spontaneously immune-mediated diabetes.

Project description:A humanized mouse strain that develops spontaneously immune-mediated diabetes.

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A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

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The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype.

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A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor.

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A humanized mouse model to study type 1 diabetes

2017-07-19 | GSE101551 | GEO

Entire CD3?, ?, and ? humanized mouse to evaluate human CD3-mediated therapeutics.

Project description:T cell-mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the therapeutics, usually monoclonal antibodies specific to human CD3, cannot react to mouse endogenous Cd3. Although immunodeficient mice transfused with human hematopoietic stem or precursor cells, known as humanized mice, are available for these studies, mice humanized in this manner are not completely immune competent. In this study we have succeeded in establishing a novel mouse strain in which all the three components of the Cd3 complex - Cd3?, Cd3?, and Cd3? - are replaced by their human counterparts, CD3E, CD3D, and CD3G. Basic immunological assessments have confirmed that this strain of human CD3 EDG-replaced mice are entirely immune competent, and we have also demonstrated that a bispecific antibody that simultaneously binds to human CD3 and a tumor-associated antigen (e.g. ERBB2 or GPC3) can be evaluated in human CD3 EDG-replaced mice engrafted with tumors. Our mouse model provides a novel means to evaluate the in vivo efficacy of human CD3-mediated therapy.

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