Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury

We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF), an epithelial tissue repair factor, can ameliorate graft-ver sus-host disease (GVHD) after intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation (BMT). To determine whether this effect was dependent on a KGF-mediated mechanism affecting repair of condi tioning-induced epithelial cell injury, we studied GVHD in the absence of c onditioning using BALB/c severe combined immune-deficient (SCID) recipients given C57BL/6 T cells. KGF (5 mg/kg per day, subcutaneously) given either before or after T-cell transfer enhanced body weights and extended survival . KGF-treated recipients had elevated serum levels of the Th2 cytokine inte rleukin 13 (IL-13) on day 6 after T-cell transfer concomitant with reduced levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha ) and interferon gamma (IFN-gamma). A 3-day KGF pretreatment also depressed the secondary in vitro mixed lymphocyte response (MLR) of C57BL/6 splenocy tes taken 7 days after in vivo alloimmunization with irradiated BALB/c sple en cells. To determine whether KGF would inhibit host-antidonor-mediated BM rejection, pan-T-cell-depleted BALB/c BM cells were infused into sublethal ly irradiated C57BL/6 mice and administered KGF either before or before and after BMT. Surprisingly, all KGF schedules tested actually resulted in enh anced alloengraftment. The presence of KGF receptor on donor antihost allor eactive T cells could not be detected by binding studies with radiolabeled KGF, reverse transcriptase-polymerase chain reaction, and Western blotting. Therefore, the mechanism of action of KGF on inhibiting T-cell-mediated im mune effects may not be due to a direct effect of KGF on T cells. These stu dies demonstrate that KGF, by mechanisms independent of repair of condition ing induced injury, has great potential as an anti-GVHD therapeutic agent w ith the added benefit of inhibiting the rejection of pan-T-cell-depleted do nor BM allografts. (Blood. 2000;96:4350-4356) (C) 2000 by The American Soci ety of Hematology.