title: Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model.
abstract: BACKGROUND
  Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft.
  
  
  METHODS
  Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group.
  
  
  RESULTS
  All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle.
  
  
  CONCLUSIONS
  Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.
authors.affiliation: Pittsburgh, Pa. From the Division of Plastic and Reconstructive Surgery, the Thomas E. Starzl Transplantation Institute, and the Departments of Pathology, Dermatology, Immunology, and Surgery, University of Pittsburgh School of Medicine, and the Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Solari
authors.forename: Kia M
authors.initials: KM
authors.lastname: Washington
authors.forename: Justin M
authors.initials: JM
authors.lastname: Sacks
authors.forename: Theresa
authors.initials: T
authors.lastname: Hautz
authors.forename: Jignesh V
authors.initials: JV
authors.lastname: Unadkat
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Horibe
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: W P Andrew
authors.initials: WPA
authors.lastname: Lee
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control*; D006614:Hindlimb; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D012867:Skin / Q000187:drug effects / Q000276:immunology; D016038:Skin Transplantation / Q000009:adverse effects*; D016559:Tacrolimus / Q000008:administration & dosage*; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus