title: Single Implantable FK506 Disk Prevents Rejection in Vascularized Composite Allotransplantation.
abstract: BACKGROUND
  In vascularized composite allotransplantation, medication nonadherence leads to increased acute rejections. Improving medication adherence would improve overall allograft survival. Regionally delivered immunosuppression, targeted to sites of allorecognition, may reduce or eliminate the need for daily systemic immunosuppression.
  
  
  METHODS
  The authors developed biodegradable FK disks containing FK506-loaded double-walled microspheres and tested their efficacy at preventing rejection in a Brown-Norway-to-Lewis rat hindlimb transplantation model. In some experimental group animals, one FK disk was implanted subcutaneously either in native nontransplanted leg or in a transplanted allograft. Regular blood FK506 levels were measured. The endpoint was 180-day allograft survival or grade 3 rejection. At the endpoint, tissue FK506 levels were measured and mixed lymphocytic reaction was performed.
  
  
  RESULTS
  A single FK disk maintained systemic blood FK506 levels between 5 and 15 ng/ml for 146 ± 11.1 days. After that, the levels declined to less than 5 ng/ml through the endpoint. There was significantly increased FK506 concentration in groin lymph nodes draining the implanted FK disk. Compared with other groups, animals with an FK disk in the transplanted allograft had 100 percent allograft survival to more than 180 days despite subtherapeutic levels below 5 ng/ml. In these animals, significant T-cell hyporesponsiveness was seen in groin lymph nodes draining the FK disk compared with robust splenic T-cell proliferation.
  
  
  CONCLUSIONS
  Sustained regional immunosuppression (with a single FK506 disk) maintained the allograft by means of a high regional concentration of FK506. Notably, this was achieved at subtherapeutic blood concentrations of FK506, without any further systemic FK506 administration.
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Jignesh V
authors.initials: JV
authors.lastname: Unadkat
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Schnider
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Firuz G
authors.initials: FG
authors.lastname: Feturi
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Wakako
authors.initials: W
authors.lastname: Tsuji
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Bliley
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Solari
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Kacey G
authors.initials: KG
authors.lastname: Marra
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Gorantla
authors.affiliation: Pittsburgh, Pa.|From the Departments of Plastic Surgery, Bioengineering, and Pharmaceutical Science, School of Pharmacy, and the McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Spiess
mesh_terms: D000818:Animals; D004337:Drug Carriers; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008863:Microspheres; D051381:Rats; D011914:Rats, Inbred BN; D016559:Tacrolimus / Q000627:therapeutic use*; D063986:Vascularized Composite Allotransplantation
chemical_list: D004337:Drug Carriers; D007166:Immunosuppressive Agents; D016559:Tacrolimus