title: Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury.
abstract: We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF), an epithelial tissue repair factor, can ameliorate graft-versus-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 conditioning-induced epithelial cell injury, we studied GVHD in the absence of conditioning 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 interleukin 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 splenocytes taken 7 days after in vivo alloimmunization with irradiated BALB/c spleen cells. To determine whether KGF would inhibit host-antidonor-mediated BM rejection, pan-T-cell-depleted BALB/c BM cells were infused into sublethally irradiated C57BL/6 mice and administered KGF either before or before and after BMT. Surprisingly, all KGF schedules tested actually resulted in enhanced alloengraftment. The presence of KGF receptor on donor antihost alloreactive 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 immune effects may not be due to a direct effect of KGF on T cells. These studies demonstrate that KGF, by mechanisms independent of repair of conditioning-induced injury, has great potential as an anti-GVHD therapeutic agent with the added benefit of inhibiting the rejection of pan-T-cell-depleted donor BM allografts. (Blood. 2000;96:4350-4356)
authors: Department of Pediatrics, Heme/Onc/BMT Division, University of Minnesota, Minneapolis 55455, USA. panos001@tc.umn.edu
authors: A
authors: A
authors: Panoskaltsis-Mortari
authors: P A
authors: PA
authors: Taylor
authors: J S
authors: JS
authors: Rubin
authors: A
authors: A
authors: Uren
authors: L A
authors: LA
authors: Welniak
authors: W J
authors: WJ
authors: Murphy
authors: C L
authors: CL
authors: Farrell
authors: D L
authors: DL
authors: Lacey
authors: B R
authors: BR
authors: Blazar
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000528:radiation effects; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006133:Growth Substances / Q000494:pharmacology / Q000627:therapeutic use*; D007114:Immunization; D007371:Interferon-gamma / Q000097:blood; D018793:Interleukin-13 / Q000097:blood; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D011828:Radiation Chimera; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D018418:Th2 Cells / Q000378:metabolism; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D018793:Interleukin-13; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D007371:Interferon-gamma