Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia.
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.
Hill
G R
GR
Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Teshima
T
T
Gerbitz
A
A
Pan
L
L
Cooke
K R
KR
Brinson
Y S
YS
Crawford
J M
JM
Ferrara
J L
JL
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D004064:Digestive System / Q000293:injuries; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D006087:Graft vs Host Reaction / Q000187:drug effects / Q000276:immunology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*; D014916:Whole-Body Irradiation
D015703:Antigens, CD; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide