A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

Luce, Siméon; Guinoiseau, Sophie; Gadault, Alexis; Letourneur, Franck; Nitschké, Patrick; Bras, Marc; Vidaud, Michel; Charneau, Pierre; Larger, Étienne; Colli, Máikel Luís; Eizirik, Décio L.; Lemonnier, François

doi:10.3389/fimmu.2021.748679

Cited by 5 publications

(4 citation statements)

References 73 publications

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“…Humanized mouse models, which are mice with a "human-like" immune system have proven to be an excellent platform to bridge the gap between preclinical mouse models and clinical studies by enabling researchers to assess the efficacy of treatments on human immune cells in a more physiological context than provided by cell culture [3]. In the T1DM field several excellent preclinical experimental approaches have also been proposed [4][5][6], although spontaneous T1DM disease development and sufficient similarity to human disease are still challenges.…”

Section: Preclinical Murine Models Of T1dmmentioning

confidence: 99%

The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes: An Immune Cell Perspective

Buckle¹,

Forbes²

2023

Type 1 Diabetes in 2023 - From Real Practice to Open Questions

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Type 1 diabetes (T1DM) is an autoimmune disorder resulting in destruction of the insulin producing pancreatic β-cells that reside in the Islets of Langerhans. Despite significant progress in the understanding of T1DM pathogenesis, some fundamental contributing mechanisms remain to be fully elucidated. The receptor for advanced glycation end products (RAGE) and its ligands are increasingly believed to play a role in the development of T1DM, but this is not well understood. The location of RAGE gene is shared with major T1DM genetic susceptibility loci on chromosome 6 and polymorphism of this region confers risk for T1DM. Furthermore, changes in RAGE expression on and ligand binding by immune cells, in particular T cells, are associated with pro-inflammatory and autoimmune profiles key for T1DM development. Indeed, in murine models for T1DM, targeting of RAGE or its ligands decreased onset and severity of disease including favorable immune cell profiles and infiltration and improved beta cell insulin secretory function. Further understanding of RAGE expression and signaling in immune cells in T1DM will provide valuable insights into disease pathogenesis and therapy development. This chapter will discuss what is currently known about RAGE in the immune cells integral for the pathogenesis of T1DM.

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Section: Preclinical Murine Models Of T1dmmentioning

confidence: 99%

The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes: An Immune Cell Perspective

Buckle¹,

Forbes²

2023

Type 1 Diabetes in 2023 - From Real Practice to Open Questions

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“…These efforts are described in other publications. [147,[149][150][151][152] [88] Copyright 2020, The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).…”

Section: Lack Of Correlative Clinical Models Present a Major Challeng...mentioning

confidence: 99%

Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity

Ackun-Farmmer

Jewell

2023

Advanced NanoBiomed Research

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Motivating the Development of Antigen-Specific ImmunotherapiesAutoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CD), and many others develop when the immune system mistakenly recognizes self-antigens as foreign, resulting in an orchestrated attack of host tissues. MS is a demyelinating disease that affects the central nervous system (CNS), RA is a chronic inflammatory joint disorder that can affect other tissues and organs, and T1D is a chronic condition whereby the pancreas produces little or no insulin. Complications from T1D can impact other tissues and organs. CD is a chronic digestive autoimmune disease that is triggered by gluten consumption, resulting in damage to the small intestine. The exact causes of autoimmune diseases are only partially understood. However, biological sex, [1,2] genetics, [3,4] existing autoimmune disease, [5] lifestyle (i.e., smoking, obesity, and exposure), [6][7][8][9][10][11] certain medications, [12] and certain infections [13][14][15][16][17] have been linked with the development of autoimmune diseases. For example, most autoimmune diseases affect more female than male patients, but the reason for this bias is unclear. [1] In MS, risk gene variant, HLA-DRB1*15:01, increases risk for patients, [18] and infection by Epstein-Barr virus (EBV) is associated with increased risks of MS, RA, and other autoimmune diseases. [13][14][15] These are currently no cures for these diseases, creating chronic battles that affect patient quality of life and require life-long compliance. Owing to the complex immunopathology of autoimmune disease, current treatments, even monoclonal antibodies, are not able to distinguish between normal and self-reactive cells. These therapies exploit distinct parenteral (e.g., intravenous [IV], subcutaneous [S.C.], intramuscular (IM), intradermal (ID), transdermal, intranodal) or mucosal (e.g., oral, intranasal (IN), pulmonary, sublingual, ocular) delivery routes to reduce disease severity. [19][20][21][22][23] For example, Ocrelizumab (Ocrevus, Genentech), a recombinant antibody that binds to CD20 on B lymphocytes to treat MS, is administered via IV injection and associated with risk of infections and allergic responses in certain patients. [19] Methotrexate, a first-line disease-modifying antirheumatic drug, is provided orally or S.C. but can lead to liver and lung damage and

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“…In the YES mouse model, knocked out for mouse MHC class I and II and double transgenic for HLA-A2/DQ8, murine T cells that developed on transgenic HLAs showed a significant response to human insulin peptides after immunization [ 210 ]. In a more recent version, human insulin and B7.1 molecules were also expressed in β-cells, and the mice (both males and females) spontaneously developed diabetes between 10 and 30 weeks of age [ 211 ]. In another mouse model with transgenic expression of human GAD65 in murine pancreatic β-cells and HLA-DQ8 on murine APCs, the mouse immune system was able to destroy β-cells and induce spontaneous diabetes [ 212 ].…”

Section: Applications Of His Models To Study Immune Tolerance and Autoimmune Processesmentioning

confidence: 99%

Modeling human T1D-associated autoimmune processes

Khosravi‐Maharlooei

Madley

Borsotti

et al. 2022

Molecular Metabolism

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Background Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. Scope of review Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. Major conclusions To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.

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A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

Cited by 5 publications

References 73 publications

The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes: An Immune Cell Perspective

The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes: An Immune Cell Perspective

Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity

Modeling human T1D-associated autoimmune processes

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