We previously demonstrated that in vivo engagement of CD137, a member of TNF receptor superfamily, can delete alloreactive CD4+ T cells through the induction of activation-induced cell death (AICD), thus preventing chronic GVHD in the DBA/2unirradiated (C57BL/6 x DBA/2)F1 (BDF1) chronic GVHD model. In this study, we further showed that in vivo engagement of CD137 was highly effective in triggering AICD of donor CD8+ T cells as well as donor CD4+ T cells in the C57BL/7unirradiated BDF1 acute GVHD model. Even though CD137 stimulation facilitated lethal GVHD in mice preconditioned with a higher dosage of total body irradiation, CD137 stimulation rather completely prevented acute GVHD without impairing donor cell engraftment in mice preconditioned with a lower dosage of total body irradiation (200 rad). Further analysis showed that engrafted donor T cells followed by CD137 stimulation did not exhibit alloreactivity to host alloantigens, including skin graft, further demonstrating that CD137 stimulation completely removed alloreactive donor T cells from the mature donor T cell pool transferred into the host. Interestingly, however, CD137 stimulation heightened a GVL effect. Our result suggest that CD137 stimulation increase the activity of donor T cells against weak tumor antigens, while deleting donor T cells responding to strong alloantigens. In sum, CD137 stimulation may be used as a GVHD prophylaxis in a parent-into-F1 GVHD setting.
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