Role of tumor necrosis factor-α in graft-versus-host disease and graft-versus-leukemia responses

AbstractTumor necrosis factor-alpha (TNF-α) antagonist therapy has proven effective in inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. There is substantial evidence that TNF-α also plays a role in the development of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, which along with leukemia relapse remains one of the 2 major impediments to success of the approach. Using a recently developed potent rat/mouse chimeric monoclonal antibody directed against murine TNF-α (CNTO2213), the authors investigated the effect of TNF-α blockade on GVHD mediated by either CD4+ or CD8+ donor T cells. The results indicated that the treatment had only a moderate effect on both a CD8+ T cell-mediated major histocompatibility complex-matched GVHD model involving multiple minor histocompatibility antigens and a p→F1 acute GVHD model directed against a haplo-mismatched major histocompatibility complex barrier involving both CD4+ and CD8+ T cells. In contrast, treatment with the anti-TNF-α antibody had a highly significant effect (100% survival rate) on the CD4+ T cell-mediated component of this latter model. Importantly, anti-TNF-α antibody did not block the development of a graft-versus-leukemia effect against a murine myeloid leukemia challenge in either a syngeneic or allogeneic p→F1 setting. This suggests that the inhibition of TNF-α during allogeneic hematopoietic cell transplantation may be able to diminish the inflammatory GVHD reaction without hindering effective graft-versus-leukemia responses