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

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

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

Blood. 1996 Feb 15;87(4):1232-7. Unique Identifier : AIDSLINE MED/96190035
Graubert TA; Russell JH; Ley TJ; Department of Internal Medicine and Genetics, Washington; University Medical School, St Louis, MO 63110, USA.

Abstract: 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+ effectors. 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 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.

Keywords: Animal Bone Marrow Transplantation/IMMUNOLOGY Cytotoxicity, Immunologic CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Graft vs Host Disease/*IMMUNOLOGY *Graft Rejection Immunity, Cellular Killer Cells, Natural/*IMMUNOLOGY Mice Mice, Inbred C57BL Serine Proteinases/*PHYSIOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Survival Analysis T-Lymphocytes, Cytotoxic/*IMMUNOLOGY JOURNAL ARTICLE
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M9681224

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