Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses.
Tumor necrosis factor-alpha (TNF-alpha) antagonist therapy has proven effective in inflammatory conditions such as rheumatoid arthritis and Crohn's disease. There is substantial evidence that TNF-alpha 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-alpha (CNTO2213), the authors investigated the effect of TNF-alpha 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-->F(1) 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-alpha antibody had a highly significant effect (100% survival rate) on the CD4(+) T cell-mediated component of this latter model. Importantly, anti-TNF-alpha 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-->F(1) setting. This suggests that the inhibition of TNF-alpha during allogeneic hematopoietic cell transplantation may be able to diminish the inflammatory GVHD reaction without hindering effective graft-versus-leukemia responses.
Korngold
Robert
R
Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA. R.Korngold@mail.jci.tju.edu
Marini
Joseph C
JC
de Baca
Monica E
ME
Murphy
George F
GF
Giles-Komar
Jill
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha