title: Donor T cell-derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation.
abstract: Previous studies in murine bone marrow transplantation (BMT) models using neutralizing anti-tumor necrosis factor (TNF) antibodies or TNF receptor (TNFR)-deficient recipients have demonstrated that TNF can be involved in both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). TNF in these GVHD and GVL models was thought to be primarily produced by activated monocytes and macrophages, and the role of T cell-derived TNF was not determined. We used TNF(-/-) mice to study the specific role of TNF produced by donor T cells in a well-established parent-into-F1 hybrid model (C57BL/6J-->C3FeB6F1/J). Recipients of TNF(-/-) T cells developed significantly less morbidity and mortality from GVHD than recipients of wild-type (wt) T cells. Histology of GVHD target organs revealed significantly less damage in thymus, small bowel, and large bowel, but not in liver or skin tissues from recipients of TNF(-/-) T cells. Recipients of TNF(-/-) T cells which were also inoculated with leukemia cells at the time of BMT showed increased mortality from leukemia when compared with recipients of wt cells. We found that TNF(-/-) T cells do not have intrinsic defects in vitro or in vivo in proliferation, IFN-gamma production, or alloactivation. We could not detect TNF in the serum of our transplant recipients, suggesting that T cells contribute to GVHD and GVL via membrane-bound or locally released TNF.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Schmaltz
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Muriglan
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Kappel
authors.forename: Jimmy A
authors.initials: JA
authors.lastname: Rotolo
authors.forename: Eric T
authors.initials: ET
authors.lastname: Ricchetti
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Willis
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology; D007420:Intestine, Large / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D007942:Leukemia, Experimental / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000473:pathology; D014019:Tissue Donors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha