title: Statins induce immunosuppressive effect on heterotopic limb allografts in rat through inhibiting T cell activation and proliferation.
abstract: Long-term use of immunosuppressive agents could bring many side effects. Recently, 3-Hydroxy-3-methyl-gutaryl coenzyme A reductase inhibitors (statins) have been reported to be immunomodulatory besides lowering serum cholesterol level. The aim of this study was to investigate the effects of statins on composite tissue allografts and T lymphocyte in vivo and in vitro. Rats were divided into 5 groups: syngeneic transplantation group (Lewis-Lewis); allogeneic control group (Brown Norway-Lewis, no treatment); low-dose statins group (15 mg /kg); high-dose statins group (30 mg /kg) and cyclosporin A group. In vivo, treatment of statins significantly prolonged allografts survival as compared to control group. Histological findings further supported these clinical results and demonstrated less extent of rejection. Immunohistochemical analysis showed that there was a remarkably reduced T cells infiltration in statins groups. Moreover, the serum levels of IL-2 and IFN-gamma were decreased after statins therapy, while these in control group increased significantly. Meanwhile, transcriptional activities of IL-2 and IFN-gamma were also dramatically down-regulated after statins treatment. In vitro, mixed lymphocyte reaction assay was performed and the results revealed lymphocyte proliferation was inhibited by statins in a dose-dependent manner. Furthermore, administration of statins exhibited inhibitory effects on CD3/CD28 mediated T cell activation and proliferation. Besides, the results demonstrated that statins significantly down-regulated mRNA expression and suppress cytokine production of IL-2 and IFN-gamma in vitro. In conclusion, our data demonstrated that application of statins could induce immunosuppressive effect and prolong allografts survival through inhibiting activation and proliferation of T cell and reducing production of IL-2 and IFN-gamma.
authors.affiliation: Department of Plastic Surgery, the second Hospital of Harbin Medical University, XueFu Road 246, Harbin, 150086, Heilong Jiang Province, China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Nie
authors.forename: Daping
authors.initials: D
authors.lastname: Yang
authors.forename: Guofeng
authors.initials: G
authors.lastname: Liu
authors.forename: Deli
authors.initials: D
authors.lastname: Dong
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ma
authors.forename: Hailiang
authors.initials: H
authors.lastname: Fu
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zhao
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000276:immunology / Q000637:transplantation*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D007376:Interleukin-2 / Q000097:blood / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D015533:Transcriptional Activation; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012333:RNA, Messenger; D007371:Interferon-gamma