INFLAMMATORY REACTIONS INDUCED BY PRETRANSPLANT CONDITIONING - AN ALTERNATIVE TARGET FOR MODULATION OF ACUTE GVHD AND COMPLICATIONS FOLLOWING ALLOGENEIC BONE-MARROW TRANSPLANTATION

Intensity of pretransplant conditioning has been closely correlated wi th regimen related toxicity in patients receiving allogeneic bone marr ow transplantation (BMT). In this review, we summarize evidence for a direct-link between inflammatory reactions induced by irradiation and cytotoxic treatment and occurrence of acute graft-versus-host disease (GVHD) as well as endothelial complications: In our studies, de novo r elease of TNFalpha during conditioning was associated with an increase d risk of severe GVHD and mortality following BMT, whereas increased s pontaneous production of IL-10, an endogenous TNF-antagonist, prior to conditioning protected from these complications. Immunogenetic differ ences in cytokine regulation and costimulation by endotoxin proved to be important cofactors determining the extent of inflammatory cytokine release in individual patients. Pathophysiological relevance of these finding seems to be confirmed by experimental as well as first clinic al trials using TNF-antibodies and related antagonists during pretrans plant conditioning. Preclinical experiments suggest additional, cytoki ne independent inflammatory reactions induced by irradiation such as e xpression of ICAM-1 and endothelial cell apoptosis. Although the exact impact of these findings on pathophysiology of BMT related complicati ons needs further clarification by future studies, conditioning relate d inflammation as a first crucial step in induction of GvHD and compli cations has to be considered when designing new protocols for preparat ion of patients for allogeneic BMT.