Graft-versus-host disease and graft-versus-leukemia.

Allogeneic bone marrow transplantation (BMT) remains the treatment of choice for a number of malignant conditions. Much of the therapeutic potential of this procedure for these diseases relates to the graft-versusleukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer (NK) cells (1). GVL effects are closely associated, however, with graft-versus-host disease (GVHD), which remains the major limitation of allogeneic BMT. During acute GVHD, cytokine dysregulation occurs as a consequence of synergistic interactions between cells of both myeloid and lymphoid lineages (2). T cells present in the donor inoculum encounter allogeneic histocompatibility antigens on host tissues and, in the presence of IL-12, secrete the Th1 cytokines IFN-γ and IL-2 (3). IFN-γ primes monocytes and macrophages to secrete large quantities of inflammatory cytokines after stimulation by LPS (4). Together with NK cells and cytoxic T lymphocytes (CTLs), these cytokines mediate GVHD target organ damage (5). Depletion of T cells from the graft effectively prevents GVHD, but it results in the loss of the GVL effect and increases the rate of graft failure (6). An alternative approach to the prevention of acute GVHD is to retain mature T cells in the bone marrow graft but to disrupt the amplification of inflammatory cytokine effectors. With this in mind, randomized clinical trials using novel cytokine inhibitors that neutralize TNF-α and IL-1 are currently in progress as adjuncts to GVHD prophylaxis. Until recently, GVHD has been thought to occur independently of BMT conditioning. However, clinical studies have shown a correlation between GVHD incidence and total body irradiation (TBI) dose (7, 8) and conditioning regimens containing TBI compared with those containing only chemotherapy (9). The incidence of conditioning-related toxicity has also been associated with GVHD severity (10). We have recently confirmed that large doses of TBI increase GVHD severity by amplifying the dysregulation of inflammatory cytokines (11). TBI and allogeneic immune cells synergize to damage the gastrointestinal (GI) tract, thereby permitting increased translocation of LPS into the systemic circulation. This damage, together with increased production of TNF-α by host cells after TBI, leads to an increase in the morbidity and mortality of GVHD.