TOTAL-BODY IRRADIATION AND ACUTE GRAFT-VERSUS-HOST DISEASE - THE ROLEOF GASTROINTESTINAL DAMAGE AND INFLAMMATORY CYTOKINES

The influence of bone marrow transplantation (BMT) conditioning regime ns on the incidence and severity of graft-versus-host disease (GVHD) h as been suggested in clinical BMT. Using murine BMT models, we show he re an increase in GVHD severity in several donor-recipient strain comb inations after intensification of the conditioning regimen by increasi ng the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. In creased GVHD was mediated by systemic increases in tumor necrosis fact or alpha (TNF alpha). Histologic analysis of gastrointestinal tracts s howed synergistic damage by increased TBI and allogeneic donor cells t hat permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha fro m macrophages primed by the GVH reaction. In addition, macrophages iso lated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increa sed macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequen t severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS sti mulation of primed macrophages may limit the severity of GVHD after in tensive conditioning for allogeneic BMI. (C) 1997 by The American Soci ety of Hematology.