THE ROLE OF CELL-MEDIATED CYTOTOXICITY IN ACUTE GVHD AFTER MHC-MATCHED ALLOGENEIC BONE-MARROW TRANSPLANTATION IN MICE

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for se veral decades: We transplanted T cells from Fas-Ligand (FasL)-defectiv e and perform-deficient mutant donor mice into lethally irradiated MHC -matched allogeneic recipient mice to characterize the role of cell-me diated cytotoxicity in GVHD. Although recipients of allogeneic FasL-de fective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perform-deficient allogeneic donor T cells developed sig ns of acute GVHD, but the time of onset was significantly delayed. The se findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-m ediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD- associated tissue damage.