title: Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 x DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 microg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kuroiwa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Takehito
authors.initials: T
authors.lastname: Imado
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Sano
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002908:Chronic Disease; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D015847:Interleukin-4 / Q000235:genetics; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000473:pathology; D008181:Lupus Nephritis / Q000517:prevention & control*; D018655:Lymphocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D009994:Osmolar Concentration; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000209:etiology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D018418:Th2 Cells / Q000473:pathology; D014162:Transfection
chemical_list: D000974:Antibodies, Antinuclear; D018106:CD28 Antigens; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D012333:RNA, Messenger; D015847:Interleukin-4; D017228:Hepatocyte Growth Factor; D004247:DNA