Specific autoimmune infiltration of stem cell-derived beta cell grafts in type 1 diabetes patient-derived personalized immune mice but not in PBMC-humanized mice 2343

Abstract Description In vivo models for human Type 1 Diabetes (T1D) that reflect the heterogeneity of predisposing genes are urgently needed. We developed a personalized immune (PI) mouse model where NSG mice receive hematopoietic stem cells (HSCs) from T1D or healthy control (HC) donors, along with a fetal thymic graft sharing T1D HLA risk alleles with both donors. Immune abnormalities reported in T1D patients are recapitulated in T1D-derived PI mice. To assess autoimmune β cell destruction, autologous iPSC-derived or histocompatible Embryonic Stem (ES)-derived β cells were transplanted into PI mice. β cell graft function was compared to that in unreconstituted NSG mice and NSG mice that received PBMCs from T1D or HC donors (PBMC-NSG mice). A decline in human C-peptide over time was observed only in T1D and not in HC PI mice. In contrast, C-peptide levels of PBMC-NSG mice declined following injection of either HC or T1D PBMCs in association with immune infiltration of iPSC/ES β cell grafts, potentially due to responses against stem cell-derived neoantigens. Conversely, only T1D PI mice exhibited spontaneous infiltration of autologous β cells by T cells and macrophages, while HC PI mice maintained tolerance to autografts. Spontaneous infiltration of T1D grafts highlights T1D autoimmunity as HSC-intrinsic and genetically driven. Thus, T1D patient-derived immune systems in PI mice mediate β cell autoimmunity, providing a unique model to investigate T1D pathogenesis and potential therapies. Funding Sources Supported by NIDDK UC4DK104207; NIDDK U01DK123559; NIAID R01AI177872; Breakthrough T1D JDRF 2-SRA-2022-1220-S-B. Topic Categories Basic Autoimmunity (BA)