Graft-versus-host disease (GVHD) induced by transplant-derived T cells represents a major complication after allogeneic
bone marrow transplantation (BMT). However, these T cells support engraftment, early T-cell immunity, and mediate the graft-versus-
tumor (GVT) effect. Cytotoxic effector functions by transplanted T cells are predominantly mediated by the
perforin/
granzyme and the CD95/
CD95L system.
APG101, a novel recombinant human fusion
protein consisting of the extracellular domain of CD95 and the Fc domain of an
IgG1 antibody inhibited CD95L-induced apoptosis without interfering with T-cell function in vitro and was therefore tested for its ability to prevent GVHD in murine BMT models across minor or major histocompatibility barriers. Starting
APG101 treatment either 1 day before or 6 days after
transplantation effectively reduced clinical GVHD and rescued survival between 60% and 100% if GVHD was
CD95L mediated.
APG101 did not interfere with the GVT effect, because P815
mastocytoma and most importantly primary Bcr-Abl-transformed
B-cell leukemias were completely eradicated by the
alloantigen-specific T cells. Phenotype and homing of
alloantigen-specific T cells or their
perforin/
granzyme-mediated cytotoxicity and proliferative capacity were not affected by
APG101 treatment suggesting that
APG101 therapy might be useful in GVHD prophylaxis without impairing T-cell function and most importantly preserving GVT activity.