Program in Molecular Medicine, Diabetes Center of Excellence
Disease Modeling | Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Immune System Diseases | Nutritional and Metabolic Diseases | Translational Medical Research
BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to beta-cell antigens and progressive destruction of insulin-producing beta-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.
Autoimmunity, Beta cell destruction, Disease modeling, Humanized mice, In vitro models, Type 1 diabetes, UMCCTS funding
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Copyright 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Khosravi-Maharlooei M, Madley R, Borsotti C, Ferreira LMR, Sharp RC, Brehm MA, Greiner DL, Parent AV, Anderson MS, Sykes M, Creusot RJ. Modeling human T1D-associated autoimmune processes. Mol Metab. 2022 Feb;56:101417. doi: 10.1016/j.molmet.2021.101417. Epub 2021 Dec 10. PMID: 34902607; PMCID: PMC8739876. Link to article on publisher's site
Khosravi-Maharlooei M, Madley R, Borsotti C, Ferreira LM, Sharp RC, Brehm MA, Greiner DL, Parent AV, Anderson MS, Sykes M, Creusot RJ. (2021). Modeling human T1D-associated autoimmune processes. UMass Center for Clinical and Translational Science Supported Publications. https://doi.org/10.1016/j.molmet.2021.101417. Retrieved from https://escholarship.umassmed.edu/umccts_pubs/283
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