PROGRESSIVE ACCUMULATION OF BACTERIAL LIPOPOLYSACCHARIDE IN-VIVO DURING MURINE ACUTE GRAFT-VERSUS-HOST DISEASE

In a previous report the authors demonstrated that acute graft-versus- host disease (GVHD) was associated with pathologic amounts of tumour n ecrosis factor alpha (TNF-alpha) and the appearance of lipopolysacchar ide (LPS) in the blood of GVH reactive mice just prior to death. In th is study the authors have investigated the kinetics of LPS accumulatio n in different organs during the course of acute GVHD using a murine m odel. Unirradiated C57BL/6xAF1 (B6AF(1)) mice were transplanted with C 57BL/6 (B6) lymphoid cells and killed at predetermined times after tra nsplantation for LPS analysis. Control animals were injected with eith er 60x10(6) B6AF1 lymphoid cells (syngeneic) or 60x10(6) irradiated (2 000 rad) CBA lymphoid cells (allogeneic). Lipopolysaccharide began to appear in the liver and the spleen of GVH reactive mice from day 2 pos t-transplant and by day 10 all GVH reactive mice tested positive for h epatic and splenic LPS. Low levels of LPS were detected in some contro l mice from days 2 to 10 post-transplant but LPS was never detected af ter day 10 in control groups. Total hepatic and splenic LPS in acute G VH reactive mice peaked at a time coincident with the appearance of LP S in the serum and with the onset of mortality. These results demonstr ate that tissue levels of LPS increase throughout the course of acute GVHD and are sufficient to trigger the release of pathologic amounts o f TNF-alpha from primed macrophages resulting in the cachexia and mort ality associated with acute GVHD in this model.