Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function
Takanori Kuroiwa, Eizo Kakishita, Teruaki Hamano, Yasuro Kataoka, Yoshifumi Seto, Nobuo Iwata, Yasufumi Kaneda, Kunio Matsumoto, Toshikazu Nakamura, Takahiro Ueki, Jiro Fujimoto, Tsuyoshi Iwasaki
Takanori Kuroiwa, Eizo Kakishita, Teruaki Hamano, Yasuro Kataoka, Yoshifumi Seto, Nobuo Iwata, Yasufumi Kaneda, Kunio Matsumoto, Toshikazu Nakamura, Takahiro Ueki, Jiro Fujimoto, Tsuyoshi Iwasaki
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Article

Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function

Abstract

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-γ and TNF-α 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.

Authors

Takanori Kuroiwa, Eizo Kakishita, Teruaki Hamano, Yasuro Kataoka, Yoshifumi Seto, Nobuo Iwata, Yasufumi Kaneda, Kunio Matsumoto, Toshikazu Nakamura, Takahiro Ueki, Jiro Fujimoto, Tsuyoshi Iwasaki

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Figure 1

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Experimental protocol and effect of HGF on intestinal injury. (a) Schedu...
Experimental protocol and effect of HGF on intestinal injury. (a) Schedule for induction of GVHD and injection of HGF-HVJ liposomes or PBS. Top: Nonlethal GVHD model. GVHD was induced by injection of 108 spleen cells harvested from B6 donors into nonirradiated BDF1 mice. From the time of GVHD induction, Gluteal muscles of BDF1 mice were injected either with HVJ liposomes containing 8 μg of human HGF expression vector (HGF-HVJ liposomes) or with PBS (GVHD control). Gene transfer was repeated once a week after GVHD induction. Bottom: Lethal GVHD model. For the induction of lethal GVHD, recipient BDF1 mice were exposed to 900 cGy of TBI, and bone marrow cells (5 × 106) plus spleen cells (2 × 107) from B6 donors were injected. HGF gene transfer was repeated once a week for 3 weeks after induction of GVHD. i.m., intramuscularly; i.v., intravenously. (b) Nonirradiated BDF1 mice were injected intravenously with 108 spleen cells from B6 mice. HGF-HVJ liposomes (8 μg) were administered intramuscularly on day 0 and day 7 after induction of GVHD. Animals were sacrificed after 2 weeks of GVHD, and the intestines were removed. The length of villi in the small intestine was measured using a calibrated lens to study at least 15–20 complete and straight villi per slide in five untreated control mice, five GVHD control mice injected with PBS, and five GVHD mice injected with HGF-HVJ liposomes. Data represent the mean ± SD of five mice. AP < 0.05. (c) Hematoxylin and eosin staining of the small intestine in GVHD mice with or without HGF gene therapy. ×200. (d) Apoptosis of small intestinal epithelial cells. The TUNEL method was used to detect apoptotic cells. ×200. (e) Hematoxylin and eosin staining of the large intestine. ×200.