TNF RECEPTOR P55 CONTROLS EARLY ACUTE GRAFT-VERSUS-HOST DISEASE

Allogeneic bone marrow transplantation is frequently associated with g raft-vs-host disease (GVHD). To understand the effector mechanisms of GVHD, we investigated the role of the TNF receptor p55 (TNFRp55), whic h is known to be important in inflammation and cytotoxicity. After the transplantation of allogeneic bone marrow and spleen cells to lethall y irradiated mice, all wild-type recipients developed early lethal GVH D within 1 wk, whereas TNFRp55-deficient recipients had much reduced G VHD and survived for at least 3 wk. No defect in alloantigen presentat ion was found, since T cell proliferation and cytotoxicity were simila r to allogeneic wild-type and TNFRp55-deficient stimulator and target cells. Also, TNF alpha release did not differ significantly between th e two types of recipients. Therefore, early acute GVHD in wild-type mi ce was primarily due to TNFRp55-mediated tissue damage. Interestingly, lethal GVHD was not entirely dependent upon the TNFRp55. In experimen tal conditions using sublethal irradiation and high donor spleen cell numbers, TNFRp55-deficient recipient mice developed lethal GVHD with s imilar kinetics and frequency as the control mice. These data suggest that the effector mechanisms leading to organ damage in murine acute G VHD can be dissected in a cytokine pathway through the TNFRp55, as dem onstrated here, and in a cellular pathway through direct interaction o f cytotoxic lymphocytes with target tissues involving perforin and Fas /Fas ligand, as reported previously.