Preferential Blockade of CD8+ T Cell Responses by Administration of Anti-CD137 Ligand Monoclonal Antibody Results in Differential Effect on Development of Murine Acute and Chronic Graft-Versus-Host Diseases

Abstract

We investigated the effect of CD137 costimulatory blockade in the development of murine acute and chronic graft-vs-host diseases (GVHD). The administration of anti-CD137 ligand (anti-CD137L) mAb at the time of GVHD induction ameliorated the lethality of acute GVHD, but enhanced IgE and anti-dsDNA IgG autoantibody production in chronic GVHD. The anti-CD137L mAb treatment efficiently inhibited donor CD8+ T cell expansion and IFN-γ expression by CD8+ T cells in both GVHD models and CD8+ T cell-mediated cytotoxicity against host-alloantigen in acute GVHD. However, a clear inhibition of donor CD4+ T cell expansion and activation has not been observed. On the contrary, in chronic GVHD, the number of CD4+ T cells producing IL-4 was enhanced by anti-CD137L mAb treatment. This suggests that the reduction of CD8+ T cells producing IFN-γ promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effective inactivation of CD8+ T cells and the lesser effect on CD4+ T cell inactivation by CD137 blockade. Intervention of the CD137 costimulatory pathway may be beneficial for some selected diseases in which CD8+ T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach will be required for intervention of CD4+ T cell function.