Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function
Takanori Kuroiwa, … , Jiro Fujimoto, Tsuyoshi Iwasaki
Takanori Kuroiwa, … , Jiro Fujimoto, Tsuyoshi Iwasaki
Published June 1, 2001
Citation Information: J Clin Invest. 2001;107(11):1365-1373. https://doi.org/10.1172/JCI11808.
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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 4

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Extramedullary hematopoiesis in GVHD mice. (a–i) Histopathological exami...
Extramedullary hematopoiesis in GVHD mice. (a–i) Histopathological examination was performed using hematoxylin and eosin–stained slides of tissue samples from the spleen (a–c), liver (d–f), and bone marrow (g–i) obtained from untreated mice (a, d, g), PBS-treated GVHD mice (b, e, h), and HGF-treated GVHD mice (c, f, i) 4 weeks after the induction of GVHD. Spleen tissue from HGF-treated GVHD mice showed marked extramedullary hematopoiesis along with numerous megakaryocytes. Liver tissue from HGF-treated GVHD mice showed numerous hematopoietic foci containing granulocyte precursor cells and erythroblasts. ×200; inset, ×400. (j) Spleen cells and liver-infiltrating mononuclear cells were obtained from untreated mice and HGF-treated GVHD mice. The number of donor-derived granulocytes was determined by multiplying the total mononuclear cell count by the H-2Kd–negative and Gr-1–positive populations. Data represent the mean ± SD of five mice. P < 0.05.