ACTIVITY OF TNF-RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) IN HEMATOLOGICAL MALIGNANCIES

T-cell cytotoxicity is primarily mediated by two cell surface proteins , Fas ligand (Fast) and tumour necrosis factor-related apoptosis-induc ing ligand (TRAIL), and intracellular perforin and granzyme granules. FasL-deficient and perforin-deficient T lymphocytes maintain cytotoxic ity but fail to induce graft-versus-host disease (GVHD) when transplan ted into mice, suggesting that GVHD) and graft-versus-tumour (GVT) eff ects can be dissociated, and that TRAIL is not involved in the pathoge nesis of GVHD. Because TRAIL could mediate a favourable GVT effect it became important to study the spectrum of its activity and to investig ate factors that can dissociate its expression from Fast, TRAIL induce d apoptosis in 11/41 (27%) tumour specimens of haematological origin c ompared to 16/41 (39%) induced by Fast, although eight specimens were sensitive to both Fast and TRAIL, no synergism was observed between th ese two ligands. TRAIL induced apoptosis in a dose and time dependent manner with an ED50 of 0.5 mu g/ml and EDmax of 1 mu g/ml. TRAIL activ ity was not reduced by the over-expression of the multidrug resistant (MDR) protein, and was not enhanced by 9-cis retinoic acid (RW), which can down-regulate bcl-2 protein. Both ligands were simultaneously up- regulated in normal peripheral blood lymphocytes in response to IL-2, IL-15 and anti-CD3 antibody whereas IL-10 had no effect, Together, our data show that (1) TRAIL can mediate cell death in a variety of human haematological malignancies, (2) resistance to TRAIL is not mediated by MDR protein, (3) the lack of synergy between TRAIL and Fast suggest s that either one is sufficient to mediate T-cell cytotoxicity, and (4 ) within the panel of cytokines tested, the expression of TRAIL and Fa st could not be dissociated.