Effects of pravastatin on murine chronic graft-versus-host disease.
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.
Yoon
Hyoung-Kyu
HK
Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Lim
Ji-Young
JY
Kim
Tae-Jung
TJ
Cho
Chul-Soo
CS
Min
Chang-Ki
CK
D000818:Animals; D018925:Chemokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D017035:Pravastatin / Q000627:therapeutic use*; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D014185:Transplantation, Isogeneic
D018925:Chemokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015778:Minor Histocompatibility Antigens; D017035:Pravastatin