Harnessing the Fas pathway for type 1 diabetes therapy (128.29)

Abstract The Fas pathway is not required for T cell activation yet loss-of-function mutation that inactivates Fas (lpr) or FasL (gld) prevents autoimmune diabetes in NOD mice without interfering with normal immune responses. However, the Fas pathway has not been considered a viable therapeutic option because these mutations also cause double negative (DN) T cell lymphoproliferation and lupus-like syndrome. Using bone marrow chimeras and adoptive transfer, we show that gld mutation on either hemopoietic or nonhemopoietic compartment is equally protective from autoimmune diabetes; however, gld mutation on hemopoietic cells is responsible for most of DN T cell lymphoproliferation. Therefore, limiting gld mutation to the nonhemopoietic tissue completely controls diabetogenicity of wild type T cells without causing lymphoproliferation. The protection is recapitulated therapeutically by treating NOD-wt mice with FasL neutralizing antibody. Anti-FasL treatment curtailed insulitis and did not lead to lupus-like disease or DN T cell lymphoproliferation. These results suggest the potential of generating a new class of immunotherapy that is based on targeting T cell apoptosis inducing ligand rather than costimulatory pathways.