Macrophage priming and lipopolysaccharidetriggered release of tumor necrosis factor α during graft-versus-host disease

Abstract

In this report we have investigated macrophage (Mφ) activity and tumor necrosis factor α (TNF-α) production during graft-vs.-host disease (GVHD). TNF-α production by Mφ requires two signals: priming of Mφ by interferon followed by triggering of TNF-α production and release by lipopolysaccharide (LPS). The state of Mφ activation was examined in nonirradiated B6AF1 recipient mice injected with either 60 × 106 (acute GVHD) or 30 × 106 (nonlethal GVHD) parental B6 lymphoid cells. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS-triggered release of significant amounts of TNF-α into the serum resulting in death of the animals within 36 h. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-α. In vitro studies demonstrated that Mφ were primed during GVHD. The level of Mφ priming was greater during acute GVHD than nonlethal GVHD since 100-fold less LPS was required to trigger killing of a TNF-α-sensitive cell line by Mφ from acute GVHD animals. The amount of TNF-α released into the serum after LPS injection increased during the course of the GVHD and was significantly greater in acute GVH-reactive mice. Endogenous LPS was detected in the serum of acute GVH-reactive animals coincident with the onset of mortality. The data provide evidence that during GVHD Mφ are primed as a result of the allogeneic reaction and that endogenous LPS therefore triggers Mφ production of TNF-α resulting in the symptoms characteristic of acute GVHD.