Abstract
Top of pageAbstract 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 |[beta]| chains (either IA|[beta]|d or IA|[beta]|k) 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 na|[iuml]|ve 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 |[beta]| chain or GFP alone as a control. 4 weeks old recipient NOD mice were lethally irradiated and reconstituted the following day with either IA|[beta]|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<0.001), suggesting that anti-PD-L1 treatment precipitates the occurrence of T1D in NOD mice reconstituted with control GFP transduced bone marrow. In contrast, all the mice that reconstituted with IA|[beta]|d-GFP transduced bone marrow and treated with control rat IgG remained normoglycemic 180 days after reconstitution at which time point our experiments terminated. Only 1 out of 12 mice reconstituted with IA|[beta]|d-GFP transduced bone marrow and treated with anti-PD-L1 treatment developed diabetes. Conclusion: Induction of molecular chimerism in NOD mice is resistant to the occurrence of T1D induced by anti-PD-L1 treatment.
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