Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia

J Clin Invest. 1999 Aug;104(4):459-67. doi: 10.1172/JCI6896.


We demonstrate an increase in graft-versus-host disease (GVHD) after experimental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy/TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) function was not altered. Histological analysis of the gastrointestinal tract demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, which permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LPS was increased in BMT recipients after Cy/TBI conditioning. Neutralization of IL-1 significantly reduced serum LPS levels and GVHD mortality, but it did not affect donor CTL activity. By contrast, neutralization of TNF-alpha did not prevent GVHD mortality but did impair CTL activity after BMT. When P815 leukemia cells were added to the bone marrow inoculum, allogeneic BMT recipients given the TNF-alpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leukemia (GVL) was due to effects on donor T cells, cohorts of animals were transplanted with T cells from either wild-type mice or p55 TNF-alpha receptor-deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells demonstrated a significant impairment in donor CTL activity after BMT and an increased rate of leukemic relapse compared with recipients of wild-type T cells. These data highlight the importance of conditioning in GVHD pathophysiology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Bone Marrow Transplantation / adverse effects
  • Bone Marrow Transplantation / immunology
  • Cyclophosphamide / pharmacology
  • Digestive System / injuries
  • Female
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Graft vs Host Reaction / drug effects
  • Graft vs Host Reaction / immunology
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor, Type I
  • T-Lymphocytes, Cytotoxic / immunology
  • Transplantation Conditioning
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*
  • Whole-Body Irradiation


  • Antigens, CD
  • Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Cyclophosphamide