IDO‐Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non‐Obese Diabetic Mice

Indoleamine 2,3‐dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non‐obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10 6 (10M) or 15 × 10 6 (15M) IDO‐expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8 + T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL‐1β and cleaved caspase‐3 levels were assessed in islets co‐cultured with IDO‐expressing fibroblasts. BGLs in 83% mice treated with 15M IDO‐expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO‐expressing cells were reversed to normoglycemia. A 15M IDO‐expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8 + T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co‐cultured with IDO‐expressing fibroblasts had reduced IL‐1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO‐expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8 + T cells and Th17 cells. J. Cell. Physiol. 231: 1964–1973, 2016. © 2016 Wiley Periodicals, Inc.