Modeling immune responses to autologous and allogeneic human stem cell-derived islet grafts in vivo 2332710

Abstract

Abstract Introduction Stem cell-derived β cells offer a promising strategy for Type 1 diabetes (T1D) treatment, yet the mechanisms driving immune infiltration and graft rejection remain unclear. Using human immune system (HIS) mice, we sought to compare immune responses to autologous versus allogeneic iPSC-derived islet grafts and to test whether increasing the frequency of autoreactive T cells is sufficient to trigger insulitis in autologous grafts. Methods HIS mice were generated by engrafting human fetal liver CD34+ cells and thymic tissue with HLA-A2, -DR4 and -DQ8 alleles. Autologous or fully mismatched allogeneic iPSC-derived islets were transplanted under the kidney capsule. In subsets of mice, human T cells transduced with multiple islet antigen-reactive (IAR) TCRs were adoptively transferred. Fourteen-eighteen weeks after grafting, iPSC-derived islets were analyzed by imaging mass cytometry (IMC) and flow cytometry. Results Allogeneic grafts exhibited dense CD45+ immune infiltration, CD8+ T-cell enrichment, macrophage accumulation, and marked fibrosis and cellular proliferation. In contrast, autologous grafts showed minimal infiltration, limited fibrosis, and restricted proliferation. Despite robust engraftment and splenic persistence of IAR-TCR+ T cells, no detectable infiltration of these cells into autologous grafts was observed. Circulating human C-peptide remained stable in both settings, correlating with β-cell differentiation efficiency. Conclusion While allogeneic grafts undergo strong immune infiltration and tissue remodeling, autologous stem cell-derived islet grafts remain largely protected, even in the presence of autoreactive T cells, indicating that additional stimuli may be required to trigger autoimmune β-cell targeting in vivo. Funding Source ADA Postdoctoral Fellowship #1-25-PDF-01, JDRF 2-SRA-2022-1220-S-B Topic Categories Immune Mechanisms of Human Disease (HUM)