Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function.
Acute graft-versus-host disease (GVHD) is a major complication of bone marrow transplantation (BMT) and is characterized by hematopoietic dysfunction, immunosuppression, and tissue injury in the skin, liver, and intestinal mucosa. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, induces mitogenic and antiapoptotic activity in various epithelial cells and promotes hematopoiesis. Working in a murine model of acute GVHD, we performed repeated transfection of the human HGF cDNA into skeletal muscle and showed that this treatment inhibited apoptosis of intestinal epithelial cells and donor T-cell infiltration into the liver, thereby ameliorating the enteropathy and liver injury caused by acute GVHD. HGF also markedly suppressed IFN-gamma and TNF-alpha expression in the intestine and liver and decreased the serum IL-12. Furthermore, extramedullary hematopoiesis by donor cells was increased, and the survival rate was improved. These results suggest that HGF may be useful for controlling acute GVHD after allogeneic BMT.
Kuroiwa
T
T
Second Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
Kakishita
E
E
Hamano
T
T
Kataoka
Y
Y
Seto
Y
Y
Iwata
N
N
Kaneda
Y
Y
Matsumoto
K
K
Nakamura
T
T
Ueki
T
T
Fujimoto
J
J
Iwasaki
T
T
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000097:blood; D007422:Intestines / Q000473:pathology; D008081:Liposomes; D008099:Liver / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma