OX40 blockade delays disease progression in NOD by inducing qualitative changes in Tregs (131.1)

Abstract

Abstract Costimulatory interaction between T cells and APCs is crucial for eliciting an immune response. By blocking costimulatory pathways it is possible to prevent or slow disease progression in many autoimmune diseases. We previously investigated the role of OX40/OX40L blockade in T1D. We demonstrated that OX40 blockade suppressed T1D progression when given at late stage but before T1D symptoms. These data are consistent with the role of OX40 as secondary costimulatory molecule. In the present study we investigated the mechanisms by which OX40 blockade suppresses T1D progression in NOD. OX40 blockade marginally reduces expression of CD80 on DCs. There is a reduction in frequency of islet-reactive effector T cells in spleen and LN. Migration of effector T cells to pancreas may be inhibited since greatly reduced lymphocytic infiltrate was observed in the pancreas. Interestingly, OX40 blockade did not enhance Treg numbers in spleen, draining LN or the pancreas. We did not observe a reduction in Tregs in control animals, contrary to previous reports. In addition, FoxP3+ cells were present in and around infiltrated islets, suggesting that the number or location of Tregs may not be defective in NOD. Preliminary data suggests that OX40 blockade induces qualitative changes in Tregs by changing the regulatory mechanisms. Our data suggests that changes in function, rather than number, of Tregs may be crucial for suppressing T1D.