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Prepublished online as a Blood First Edition Paper on November 7, 2002; DOI 10.1182/blood-2002-07-2109.
Submitted July 22, 2002
Accepted October 23, 2002
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*
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Department of Pathology, Thomas Jefferson Medical Center, Philadelphia, PA, USA
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
Department of Immunology, Weill Medical College of Cornell University, New York, NY, USA
* Corresponding author; email: vandenbm{at}mskcc.org.
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 allo-activation. 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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