Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease.
The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF)alpha levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42% v 4%, P <.001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.
Krijanovski
O I
OI
Department of Pediatric Oncology, Dana Farber Cancer Institute, Children's Hospital, and Harvard Medical School, Boston, MA, USA.
Hill
G R
GR
Cooke
K R
KR
Teshima
T
T
Crawford
J M
JM
Brinson
Y S
YS
Ferrara
J L
JL
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000187:drug effects*; D006133:Growth Substances / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects / Q000528:radiation effects; D007942:Leukemia, Experimental / Q000628:therapy; D008070:Lipopolysaccharides / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D007376:Interleukin-2; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors