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Total Body Irradiation and Acute Graft-Versus-Host Disease: The Role of Gastrointestinal Damage and Inflammatory Cytokines
Geoffrey R. Hill,
James M. Crawford,
Kenneth R. Cooke,
Yani S. Brinson,
Luying Pan, and
James L.M. Ferrara
From the Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Department of Pathology, Yale University School of Medicine, New Haven, CT.
The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor  (TNF). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.
Blood, Vol. 90 No. 8 (July 15), 1997:
pp. 3204-3213
© 1997 by The American Society of Hematology.
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