Since chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT), a new strategy to prevent chronic GVHD is necessary. We previously showed that hepatocyte growth factor (HGF) protected against lethal effects of acute GVHD and promoted T cell reconstitution in murine models (

J Clin Invest
107
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1365
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2001
, Blood 2004 in press). We have now investigated whether HGF can protect against chronic GVHD. (C57BL/6 x DBA/2) F1 (BDF1) recipient mice were lethally irradiated (9 Gy) and co-transplanted with 5 x 106 bone marrow cells and 1.5 x 107 spleen cells from C57BL/6 donor mice. At the same time, mice were injected intramuscularly with 8 microgram of the human HGF gene, or with a control mock vector, every week using liposomes containing the hemagglutinating virus of Japan. Untreated GVHD recipients showed significant atrophy of the spleen and the thymus on day 56 after transplantation, while HGF treatment effectively prevented this atrophy. Splenic T cells from untreated GVHD recipients proliferated and produced significant amounts of IL-4 after being exposed to irradiated BDF1 spleen cells in vitro, while those from HGF-treated GVHD recipients did not. These results suggest that host-reactive type 2 T helper (Th2) cells were eliminated in the HGF-treated GVHD recipients by protection against thymic damage caused by acute GVHD, thereby preventing the progression to chronic GVHD. We next used DBA/2 into BDF1 models to determine the effect of HGF on another type of chronic GVHD. Chronic GVHD was induced by injection of DBA/2 spleen cells (9 x 107) into non-irradiated BDF1 mice. HGF treatment effectively prevented proteinuria and histological changes associated with glomerulonephritis. Liver sections of untreated GVHD recipients revealed prominent primary biliary cirrhosis (PBC)-like changes, as indicated by lymphocyte infiltration into the periportal area of the liver. HGF treatment effectively prevented these histological changes. HGF treatment greatly reduced the number of splenic B cells and the serum IgG and anti-DNA antibody levels. Furthermore, HGF treated GVHD recipients showed down-regulation of IL-4 mRNA expression in the spleen, liver and kidneys. IL-4 induction from DBA/2 CD4+ T cells stimulated by irradiated BDF1 CD11c+ dendritic cells (DCs) was significantly inhibited by addition of recombinant HGF (10 ng/ml) in vitro. Taken together, these results indicate that HGF can prevent chronic GVHD by eliminating host-reactive Th2 cells in the thymus, or by inhibition of Th2 cell induction by interaction with DCs.

Topics:
graft-versus-host disease, chronic, hepatocyte growth factor, liposomes, graft-versus-host disease, interleukin-4, atrophy, graft-versus-host disease, acute, allogeneic hematopoietic stem cell transplant, antibodies, dna

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2005, The American Society of Hematology
2004
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