title: Triptolide Reduces the Required Dose of Tacrolimus by Attenuating Inflammation, Enhancing Immunosuppression, and Increasing Donor Chimerism in a Heterotopic Hindlimb Transplantation Model.
abstract: BACKGROUND
  Induction of tolerance and minimizing the toxicity of immunosuppression are two fundamental goals in vascularized composite allotransplantation. Accumulating data indicate that triptolide is an agent that may have the capacity to suppress inflammation and immunologic rejection.
  
  
  METHODS
  A heterotopic hindlimb allotransplantation model from Brown Norway to Lewis rats was established and treated with different doses of tacrolimus combined with or without triptolide. Mean survival time of the transplants was monitored, and histopathologic examination of the skin was performed. The level of inflammatory cytokine interleukin-1β, interleukin-6, and tumor necrosis factor-á in peripheral blood was assayed. The percentage of T lymphocytes and its subsets was measured using flow cytometry. The level of recipient peripheral chimerism and the apoptosis of donor bone marrow cells were evaluated. The apoptotic related genes bcl-2 and Bax were detected by real-time polymerase chain reaction.
  
  
  RESULTS
  The authors' results showed that triptolide not only reduces the dose of tacrolimus required for immunosuppression, but also decreased drug side effects in terms of weight gain and diarrhea. Triptolide had an obvious effect on proinflammatory cytokine expression and T-lymphocyte proliferation in the peripheral blood. Interestingly, triptolide could increase the mixed chimerism level of recipients, possibly by inhibiting the apoptosis of transplanted bone marrow cells by means of regulation of the apoptotic genes bcl-2 and Bax.
  
  
  CONCLUSIONS
  Triptolide reduces the dose of tacrolimus required for immunosuppression by attenuating inflammation and by T-cell suppression. Furthermore, triptolide increases the chimerism level, which might contribute to acceptance of the allografts.
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: Chuan
authors.initials: C
authors.lastname: Gu
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: Xusong
authors.initials: X
authors.lastname: Luo
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: Xianyu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Shanghai, People's Republic of China; and Philadelphia, Pa.|From the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; and the Department of Orthopedic Surgery, Hospital of the University of Pennsylvania.
authors.forename: L Scott
authors.initials: LS
authors.lastname: Levin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D046528:Chimerism / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006614:Hindlimb / Q000637:transplantation*; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage* / Q000627:therapeutic use; D063986:Vascularized Composite Allotransplantation
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; C001899:triptolide; D016559:Tacrolimus