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, James L.M. Ferrara

Research output: Contribution to journalArticlepeer-review

Abstract

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 cGv. Increased GVHD was mediated by systemic increases in tumor necrosis factor α (TNFα). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysaccharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNFα 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 TNFα. 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.

Original languageEnglish (US)
Pages (from-to)3204-3213
Number of pages10
JournalBlood
Volume90
Issue number8
DOIs
StatePublished - Oct 15 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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