Costimulatory Molecule-Targeted Immunotherapy of Chronic Graft-Versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. Using the B10.D2àBalb/c (H-2^d) minor histocompatibility antigen-mismatched model which reflects clinical and pathological symptoms of human cGVHD, we show that a single injection of an agonistic monoclonal antibody (mAb) to CD137, a member of tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration and alopecia, ultimately leading to prolonged survival. The reversal is associated with markedly reduced helper type 2 CD4⁺ T cell (Th2) cytokines and increased production of the Th1 cytokine interferon-g (IFN-g). The Fas pathway is required for the therapeutic effect of anti-CD137 mAb on cGVHD. Taken together, these data indicate that anti-CD137 mAb has a therapeutic effect on cGVHD by removing Th2 cells mediating cGVHD. Our study demonstrate an agonistic mAb specific for a costimulatory molecule as a possible target for therapeutic intervention in cGVHD.