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 (He usel et al, Cell 76:977, 1994 and Shresta et al, Proc Natl Acad Sci US A 92:5679, 1995) have shown that the putative mediators of these two s yndromes, cytotoxic lymphocytes (CTL) and natural killer (NK) cells, r espectively, initiate a program of cell death (apoptosis) in susceptib le target tissues in a manner critically dependent on the serine prote ase Granzyme B (gzm B). In the present study, we have analyzed the phe notype of gzm B-deficient mice using experimental transplant models de signed to isolate their CD8(+) CTL, CD4(+) CTL, and NK compartments. W e 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 di d their wild-type littermates. This result is surprising in light of a severe defect in the ability of gzm B -/- NK cells to induce apoptosi s in susceptible targets in vitro. These in vivo data define a signifi cant role for gzm B in cytotoxicity mediated by CD8(+) CTL, but not by CD4(+) CTL. Furthermore, these results do not support a model of hybr id resistance in which NK cells play a pivotal role, (C) 1996 by The A merican Society of Hematology.