BACKGROUND: Chronic graft-versus-host disease (CGVHD) is a serious and increasingly common complication after allogeneic (allo) hematopoietic stem-cell transplantation, but currently available therapies have demonstrated limited efficacy. Furthermore, the statins have been reported to be effective in various immune-mediated disease models, but their therapeutic potentials versus CGVHD have not been determined. METHODS: We used a B10.D2→BALB/c model of CGVHD, which differs at minor histocompatibility loci, to address the therapeutic effect of statins on the development of CGVHD. Pravastatin (PST, 30 mg/kg/day) was intraperitoneally injected for 5 days per week from the day of transplantation until 4 weeks after allo hematopoietic stem-cell transplantation. RESULTS: The onset of clinical cutaneous GVHD was significantly slower in PST-treated recipients than in allo-controls (36 days vs. 25 days, respectively, P<0.05), and pathologic changes in skin disease confirmed this clinical result. Animals injected with PST showed less submucosal fibrosis in lungs than allo-controls. In addition, collagen deposition in skin and lungs was markedly attenuated by PST treatment. PST also significantly reduced protein concentrations and numbers of inflammatory and epithelial cells in bronchoalveolar lavage fluid. Significantly lower numbers of donor CD11b and CD4, but not CD8 cells, were observed in skin and bronchoalveolar lavage fluid after PST treatment. The protein concentrations of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) in skin and lungs were substantially reduced in PST-treated animals when compared with allo-controls. CONCLUSIONS: This study suggests that the CGVHD-protecting effect of PST involves the down-regulation of chemokines and the reduction of collagen synthesis.
BACKGROUND: Chronic graft-versus-host disease (CGVHD) is a serious and increasingly common complication after allogeneic (allo) hematopoietic stem-cell transplantation, but currently available therapies have demonstrated limited efficacy. Furthermore, the statins have been reported to be effective in various immune-mediated disease models, but their therapeutic potentials versus CGVHD have not been determined. METHODS: We used a B10.D2→BALB/c model of CGVHD, which differs at minor histocompatibility loci, to address the therapeutic effect of statins on the development of CGVHD. Pravastatin (PST, 30 mg/kg/day) was intraperitoneally injected for 5 days per week from the day of transplantation until 4 weeks after allo hematopoietic stem-cell transplantation. RESULTS: The onset of clinical cutaneous GVHD was significantly slower in PST-treated recipients than in allo-controls (36 days vs. 25 days, respectively, P<0.05), and pathologic changes in skin disease confirmed this clinical result. Animals injected with PST showed less submucosal fibrosis in lungs than allo-controls. In addition, collagen deposition in skin and lungs was markedly attenuated by PST treatment. PST also significantly reduced protein concentrations and numbers of inflammatory and epithelial cells in bronchoalveolar lavage fluid. Significantly lower numbers of donorCD11b and CD4, but not CD8 cells, were observed in skin and bronchoalveolar lavage fluid after PST treatment. The protein concentrations of monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T cell expressed and secreted (RANTES) in skin and lungs were substantially reduced in PST-treated animals when compared with allo-controls. CONCLUSIONS: This study suggests that the CGVHD-protecting effect of PST involves the down-regulation of chemokines and the reduction of collagen synthesis.
Authors: Jing Du; Katelyn Paz; Ryan Flynn; Ante Vulic; Tara M Robinson; Katie E Lineburg; Kylie A Alexander; Jingjing Meng; Sabita Roy; Angela Panoskaltsis-Mortari; Michael Loschi; Geoffrey R Hill; Jonathan S Serody; Ivan Maillard; David Miklos; John Koreth; Corey S Cutler; Joseph H Antin; Jerome Ritz; Kelli P MacDonald; Timothy W Schacker; Leo Luznik; Bruce R Blazar Journal: Blood Date: 2017-03-02 Impact factor: 22.113