C) 1996 Rapid Science Publishers ScL 0000S0000

" l'he curative potential of bone marrow allografts involves two components: the preparative regimen-induced killing of leukemic cells and the immune response of the donor to the recipient leukemia, which is termed the graft-ver-sus-leukemia (GVL) effect. The relative contribution of GVL to the cure of different leukemias has been quanti-ta te d in two recent International Bon e Marow Transplant Registry studies. Horowitz et al.[1] showed that the magnitude of GVL varies among different types of leukemia. Another analysis, which compared relapse rates after bone marrow transplantation (BMT) from identical twins with those from HLA-matched sib lings, demonstrated that GVL contributes between 10% to 50% of the curative potential, depending on the type of leukemia transplanted [2•]. In the past few years, an improved understanding of the principles of allogeneic immune responses in general and in graft-versus-host discase (GVHD) in particular have shed new light on the immune processes of GVL. Experimental animal BM'I'and in vitro studies with human cells point to new therapeutic strategics to improve GVL by increasing its speci-ficity and magnitude. Much research effort has been invested into determining the basis of immune recogni-tion of leukemia cells, identification of effector cells and analysis of GVI. mechanisms. Many investigators have sought to exploit differences between the allorecognition of leukemia and normal tissues to achieve GVL without GVHD. Some questions have been answered in vitro or in animal models, but therapeutic applications are still in their beginning stages.

Animal models of graft-versus-leukemia Graft-versus-leukemia was first demonstrated in rodent models. Nonimmunogenic, ie, incapable of stimulating an autologous response, lymphoid and myeloid leukemia lines have primarily been used as reproducible GVL targets. In models simulating clinical BMT, animals are first inoculated with a lethal dose of leukemia before undergoing a stem cell transplantation. The transplantation is fol-lowed by some form of experimental procedure testing a GVL effect. The mechanism of GVL differs according to whether the transplantation is carried out in a syngeneic, major, or minor histocompatibility antigen mismatched setting. CD4" cells confer GVL in major histocompatibility antigen compatible, minor histocapability antigen mis-Inatched transplants [3, 4], whereas paradoxically in transplants across major histocompatibility complex (MHC) barriers, donor CD8* T cells have an antileukemic effect and CD4 cells exert GVHD [5]. There is clear evidefor an antileukcmic effect of natural killer cells in syn-geneic l6l and allogeneic settings [7•, 8•]. The role of