Modeling human T1D-associated autoimmune processes

Abstract

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.

Stem cell-based multi-tissue platforms to model human autoimmune diabetes

“…Humanized mouse models (where human HSCs are engrafted in irradiated immunodeficient hosts) address some of these issues by incorporating human T cell progenitors. In these models (discussed in greater detail in a separate article of the HIRN review series [ 8 ]), mice are first thymectomized to prevent formation of T cells in the endogenous thymus, followed by irradiation and injection of allogeneic HSCs for long-term engraftment of human immune cells. Mice are then transplanted with SC-TEPs and assessed for engraftment of human immune cells and the formation of human T cells over months.…”

“…This strategy facilitates matching between SC-β cells and primary T cells from unrelated donors, since SC-β cells only express one HLA molecule that needs to be matched with PBMC donors. It also enables incorporating HLA-edited SC-β cells into humanized mice reconstituted with a combination of non-isogenic primary HSCs and thymus, which only need to be matched for the single HLA allele retained in SC-β cells (reviewed in detail in [ 8 ]) ( Figure 1 D). Taken together, different approaches have opened multiple paths to developing stem cell-based multi-tissue models to assess human autoimmune interactions.…”

“…Animal models of spontaneous autoimmune diabetes have provided considerable insights, leading to the formulation of interventions to prevent, halt, and even reverse disease in these animals (see [ 8 ] for a detailed review of current animal models of T1D). However, translating these approaches to humans has fallen short.…”

“…HSCs, TECs, and pancreatic cells can also be engrafted in irradiated and thymectomized immunodeficient mice to study thymic selection and subsequent immune attack of SC-islet grafts by human T cells and other immune cells ( Figure 1 D). More details on these in vitro and in vivo models are provided in a separate issue of the Human Islet Research Network (HIRN) review series [ 8 ].…”

Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children

“…Therefore, they constitute an essential part of self-tolerance mechanisms and the limitation of the inflammatory processes ( 10 ). Dysfunction or reduction of these cells might result in a breakdown of immunological tolerance and excessive immune reactions ( 11 ). In addition, Tregs function is not solely limited to suppression of T, B or NK cells activity but also participates in tissue repair and regulation of metabolism ( 12 , 13 ).…”