Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity.
Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.
Borsotti
Chiara
C
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Franklin
Anna R K
AR
Lu
Sydney X
SX
Kim
Theo D
TD
Smith
Odette M
OM
Suh
David
D
King
Chris G
CG
Chow
Andrew
A
Liu
Chen
C
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D006087:Graft vs Host Reaction / Q000276:immunology*; D017710:Lymphocyte Transfusion; D034801:Mastocytoma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology*