793. Induction of Molecular Chimerism in NOD Mice Is Resistant to the Occurrence of Type I Diabetes Induced by Blockade of the Programmed Death-1 Pathway

Introduction: We have recently shown that induction of molecular chimerism by reconstitution of NOD mice with autologous bone marrow cells reconstituted with retrovirus carrying genes encoding MHC class II β chains (either IAβd or IAβk ) from protective haplotypes can induce central deletion of auto-reactive T cells and prevent occurrence of type 1 diabetes (T1D) in NOD mice. Studies have also shown that blockade of programmed death (PD-1) pathway using anti-PD-L1 monoclonal antibody results in precipitated occurrence of T1D in naïve NOD mice. Here we show that induction of molecular chimerism in NOD mice is resistant to the occurrence of T1D induced by anti-PD-L1 antibody treatment. Methods: Bone marrow cells were harvested from 4-week old NOD mice treated with 5-fluorouracil (150mg/kg) 7 days prior and then transduced with retrovirus carrying genes encoding either a protective MHC class II β chain or GFP alone as a control. 4 weeks old recipient NOD mice were lethally irradiated and reconstituted the following day with either IAβ d -GFP or GFP transduced bone marrow. 4 weeks after reconstitution, recipient mice were treated with anti-PD-L1 monoclonal antibody or rat IgG as a control. Results: 75% of the mice reconstituted with control GFP transduced bone marrow and treated with anti-PD-L1 antibody developed diabetes by 85 days after antibody treatment (Median onset time (MOT) = 32 days), while 67% of the mice reconstituted with control GFP transduced bone marrow and treated with control rat IgG developed diabetes by 134 days (MOT = 129 days, p