Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation

Background Tumor necrosis factor-alpha (TNF-alpha) is known to be a critica l effector molecule in the pathogenesis of graft-versus-host disease (GVHD) , and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD;, Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. Methods. We studied the effect of prior chemotherapy on GVHD severity and i nflammatory cytokine generation in a well-established murine model of allog eneic BMT (B6 --> B6D2F1). Results. Three weeks after a single dose of cyclophosphamide, bone marrow a nd splenic cellularity was reduced by 50% and the production of TNF-alpha t o LPS stimulation by macrophages was also markedly impaired (both before an d after total body irradiation). Allogeneic BMT recipients previously treat ed with cyclophosphamide had significantly less GVHD;VHD and improved survi val relative to recipients previously pretreated with diluent only. This su rvival advantage was associated with reduced systemic levels of both TNF-al pha and interleukin-1 beta 7 days after BMT. This reduction occurred despit e equivalent serum levels of lipopolysaccharide, consistent with the reduct ions in TNF-alpha and interleukin-1 beta production by host macrophages aft er cyclophosphamide pretreatment. Conclusions. These data support the notion that patients entering BMT condi tioning without prior cytotoxic treatment (e,g,, patients with chronic myel oid leukemia) may be at increased risk of posttransplant complications asso ciated with excessive inflammatory cytokine production.