Unexpected role of TNF-a in graft versus host reaction (GVHR): donor-derived TNF-a suppresses GVHR via inhibition of IFN-g-dependent donor type-1 immunity

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to signi®cant morbidity and mortality. Host-derived TNF-a play a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD. On the other hand, the precise role of donor-derived TNF-a in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B63D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-a±/± C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-a±/± mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-a±/± mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-a±/± cells showed signi®cantly higher levels of serum IFN-g, which was mainly produced by donor CD8+ T cells. We also demonstrated that TNF-a de®ciency in donor spleen cells caused a marked elevation of TNF-a producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-a±/±IFN-g±/± splenic cells. Our ®ndings demonstrate, for the ®rst time, that donor-derived TNF-a suppress GVHR by inhibiting IFN-g-dependent donor type-1 immunity which is essential for host TNF-a elevation.