New strategies for prevention and treatment of graft-versus-host disease and for induction of graft-versus-leukemia effects.

Graft-versus-host disease (GVHD) continues to be a problem in allogeneic hemopoietic stem cell transplantation; however, our understanding of the basic pathophysiology of GVHD has improved. Although not all data obtained from murine or other animal models can be extrapolated to the clinic, there are leads that deserve to be pursued. The skin, intestinal tract, and liver are the 3 major target organs of GVHD and share the feature of presenting a barrier to the "environment" of the host. There is evidence that the damage inflicted to these organs, the epithelial and endothelial cells in particular, by the conditioning regimen causes a release of various cytokines and a penetration of endotoxin into the systemic circulation. According to these observations, the nonimmunologic aspects of GVHD have been likened to an inflammatory process. If this characterization is valid, blocking these nonspecific inflammatory changes would ameliorate GVHD without interfering with the graft-versus-leukemia (GVL) reaction. In fact, one study has shown a substantial amelioration of GVHD with a molecule that directly blocks endotoxin. Clinical data also suggest that patients with organ dysfunction early after transplantation that is presumed to be treatment related may benefit from preemptive interventions aimed at controlling GVHD. Furthermore, there is growing evidence that the mechanisms involved in GVHD may differ from organ to organ (for example, Fas/Fas-ligand interactions in the liver versus tumor necrosis factor alpha/receptor interactions in the intestinal tract), and from a therapeutic point of view, the time of onset of clinical GVHD may be important in choosing the appropriate therapy. Thus, combinations of interventions chosen and timed appropriately may be more effective in preventing and managing GVHD than are the standard across-the-board approaches that have been used so far. Such a strategy may also be successful in maintaining a GVL effect and possibly in incorporating direct antileukemic therapy, such as the use of cytotoxic T-cells directed at minor histocompatibility antigens, without increasing the risk of GVHD. The development of nonmyeloablative conditioning regimens and the observations on GVHD kinetics and the progression or eradication of leukemia with that strategy are likely to add new insights into how one can optimally combine various modalities to achieve engraftment, prevent GVHD, and at the same time maintain a GVL effect.