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.

Keywords: Autoimmunity; Beta cell destruction; Disease modeling; Humanized mice; In vitro models; Type 1 diabetes.

Figure 1

In vitro systems to study immune responses in T1D. Thymic organ culture systems (A) allow the study of the selection of T1D autoreactive TCRs in an in vitro system in human fetal thymus or HLA transgenic fetal mouse thymus using TCR-transduced HSCs from a fetal donor or T1D versus healthy control adult donors. The other three models presented, the inflammation- and/or islet-based microphysiological systems (B), iPSC-derived co-culture systems (C) and living pancreas slices (D), are suitable for functional assays to study the interactions of human β-cells and immune cells.

Figure 2

Mice as hosts of human immune systems. Engineering approaches and methodologies to make mice better hosts for human immune systems by improving human HSC and immune cell engraftment and facilitating the development of a diverse human immune system are shown.

Figure 3

Human immune system mouse models to study immune responses in T1D. Different sources of cells and tissues for generating HIS mice are shown. In order to study the interaction of islet β-cells with human immune cells, grafted human islets, grafted iPSC-derived β-cells or endogenous HLA transgenic (Tg) mouse pancreas can be used as the targets of the human immune system. Grafted human fetal thymus, grafted iPSC-derived thymic epithelial cells, or endogenous HLA Tg mouse thymus can support human thymopoiesis. HIS mice can be reconstituted with genetically-modified or non-modified HSCs from human fetal liver, cord blood, adult (e.g. T1D vs healthy controls) HSCs, and potential iPSC-derived HSCs. Autoreactive TCR-transduced T cells from human PBMCs or other HIS mice in the same cohort generated with autologous tissues can be adoptively transferred to recipient HIS mice to study the interaction of autoreactive T cells and β-cells. Adoptive transfer of different APCs (loaded or transduced with T1D autoantigens) from other HIS mice or differentiated from fetal liver HSCs and iPSC cell sources can be used to study the role of these cells in T1D development. Of note, iPSCs can themselves be generated from multiple sources, including not only fibroblasts but also PBMCs.