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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-07-2109.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2440-2445
TRANSPLANTATION
Donor T cell-derived TNF is required for
graft-versus-host disease and graft-versus-tumor activity after bone
marrow transplantation
Cornelius Schmaltz,
Onder Alpdogan,
Stephanie J. Muriglan,
Barry J. Kappel,
Jimmy A. Rotolo,
Eric T. Ricchetti,
Andrew S. Greenberg,
Lucy M. Willis,
George F. Murphy,
James M. Crawford, and
Marcel R. M. van den
Brink
From the Departments of Pediatrics, and Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY; the Department of
Pathology, Thomas Jefferson Medical Center, Philadelphia, PA; the
Department of Pathology, Immunology and Laboratory Medicine, University
of Florida, Gainesville; and the Department of Immunology, Weill
Medical College of Cornell University, New York, NY.
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- 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.
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