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

We investigated the effect of CD137 costimulatory blockade in the developme nt of murine acute and chronic graft-vs-host diseases (GVHD). The administr ation 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 Ig G autoantibody production in chronic GVHD. The anti-CD137L mAb treatment ef ficiently inhibited donor CD8(+) T cell expansion and IFN-gamma expression by CD8(+) T cells in both GVHD models and CD8(+) T cell-mediated cytotoxici ty against host-alloantigen in acute GVHD. However, a clear inhibition of d onor CD4(+) T cell expansion and activation has not been observed. On the c ontrary, in chronic GVHD, the number of CD4(+) T cells producing IL-4 was e nhanced by anti-CD137L mAb treatment. This suggests that the reduction of C D8(+) T cells producing IFN-gamma promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effectiv e inactivation of CD8(+) T cells and the lesser effect on CD4(+) T cell ina ctivation by CD137 blockade. Intervention of the CD137 costimulatory pathwa y may be beneficial for some selected diseases in which CD8(+) T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach wil l be required for intervention of CD4(+) T cell function.