The role of granzyme B in murine models of acute graft-versus-host disease and graft rejection

A complete molecular description of the syndromes of graft-versus-host disease (GVHD) and graft rejection could have a significant impact on clinical bone marrow transplantation. Recent in vitro experiments (Heusel et al, Cell 76:977, 1994 and Shresta et al, Proc Natl Acad Sci USA 92:5679, 1995) have shown that the putative mediators of these two syndromes, cytotoxic lymphocytes (CTL) and natural killer (NK) cells, respectively, initiate a program of cell death (apoptosis) in susceptible target tissues in a manner critically dependent on the serine protease Granzyme B (gzm B). In the present study, we have analyzed the phenotype of gzm B-deficient mice using experimental transplant models designed to isolate their CD8(+) CTL, CD4(+) CTL, and NK compartments. We found a significant impairment in class I-dependent GVHD mediated by gzm B -/- CD8(+) CTL, whereas class II-dependent GVHD was not altered using gzm B -/- CD4(+) effecters. In a hybrid resistance model, gzm B -/- hosts rejected haplo-identical marrow grafts as efficiently as did their wild-type littermates. This result is surprising in light of a severe defect in the ability of gzm B -/- NK cells to induce apoptosis in susceptible targets in vitro. These in vivo data define a significant role for gzm B in cytotoxicity mediated by CD8(+) CTL, but not by CD4(+) CTL. Furthermore, these results do not support a model of hybrid resistance in which NK cells play a pivotal role, (C) 1996 by The American Society of Hematology.