. 2019 Aug 14;198(3):326–340. doi: 10.1111/cei.13349

Table 1.

A selection of NOD mouse models facilitating studies on islet–immune interactions in T1D pathogenesis.

In vivo T1D models	Critical findings	Advantages	Shortcomings	References
NOD mouse	CD4⁺ and CD8⁺ T cells, as well as B cells, are integral to disease development	Parallels the polygenic nature of T1D and importance of MHC	Differences in disease kinetics, inflammatory infiltrate composition, islet cell architecture, pancreas morphology, and number of PLN	5, 6, 10, 11, 12, 14, 15, 16, 17, 22, 75, 120
	Islet antigen specific T cells recognize Ins B:9–23, Ins1 B5–14 and Ins1/2 A2–10	Parallels the polygenic nature of T1D and importance of MHC
	ChgA and IAPP are autoantigens and function to initiate disease and promote Th1 responses	Serves as a valuable pre‐clinical model for therapeutics	Differences in endocrine cell distribution, β‐cell regenerative capacity, and immune cell receptor expression and signaling
	Antigen specific T cells recognize post‐translationally modified epitopes which may alter binding to MHC molecules	Capacity for transgenics, adoptive transfers and lineage tracing, and intervention testing in a spontaneous model system
NOD‐scid Il2rγ ^−/− (NSG) mouse	Adoptively transferred CD8⁺ T cells from T1D donors stimulated with pooled islet antigen peptides [IGRP, IAPP, Ins, and IA‐2] traffic to the islets and produce IFN‐γ	Lack endogenous T, B and NK cells	Increased β‐cell proliferative capacity as compared to humans	6, 19
NOD‐scid Il2rγ ^−/− (NSG) mouse		Can be engrafted with human PBMCs	Alterations in homing, chemokine and cytokine use, and secondary lymphatics in xenogeneic system	6, 19
NOD‐SCID BLT HLA‐DQ8 transgenic mouse	Demonstrated the in vivo pathogenicity of human HLA‐DQ8 restricted InsB:9–23 specific CD4⁺ T cells in exacerbating insulitis and β‐cell death	Possess a complete human lymphoid and myeloid immune cell repertoire	GVHD and wasting syndrome	6, 20
NOD‐SCID BLT HLA‐DQ8 transgenic mouse		T cells are educated autologously and are HLA restricted	GVHD and wasting syndrome	6, 20
HLA‐A2.1 transgenic NOD mouse	Accelerated disease compared to nontransgenic NOD mouse	Possession of human HLA molecules allow for testing a variety of agents, including adoptive cell therapy, and ASI on human cells in vivo	Often reduced disease incidence as compared to NOD	7, 8, 9, 13
HLA‐A2.1 transgenic NOD mouse	Islet infiltrating T cells directly lyse HLA‐A2.1⁺ β‐cells
NOD.β2mnull.HHD mouse	CD8⁺ islet infiltrating T cells from HLA‐A2.1 transgenic mice target an IGRP epitope cross‐reactive to human IGRP (IGRP_228–236)
NOD.mβ2m^null.hβ2m.HLA‐A11 transgenic mouse	HLA‐A11 restricted CD8⁺ islet infiltrating T cells in HLA‐A11 transgenic mice recognize IGRP and Ins C‐peptide and are present prior to disease onset
Foxp3‐GFP‐Cre × R26‐YFPNOD transgenic mouse model	GFP^–YFP⁺Foxp3^– ex‐T_reg which lost Foxp3 were identifiable and shown to have a pro‐inflammatory phenotype	Facilitates genetic lineage tracing	Potential for off‐target Cre recombination	18
		Can identify plasticity in cell lineages and sort out these plastic populations to conduct functional studies
		Trafficking and localization can be visualized in situ

ASI = Antigen specific immunotherapy; Ins = Insulin; ChgA = Chromogranin A; IAPP = Islet Amyloid Polypeptide; IGRP = Islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein; IA‐2 = Islet antigen‐2; BLT = Bone marrow, Liver, Thymus; NK = Natural Killer; PBMCs = Peripheral blood mononuclear cells; GVHD = Graft Versus Host Disease; T_regs = regulatory T cells.