title: Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: effect on spinally grafted human neural precursor survival.
abstract: Achievement of effective, safe and long-term immunosuppression represents one of the challenges in experimental allogeneic and xenogeneic cell and organ transplantation. The goal of the present study was to develop a reliable, long-term immunosuppression protocol in Sprague-Dawley (SD) rats by: 1) comparing the pharmacokinetics of four different subcutaneously delivered/implanted tacrolimus (TAC) formulations, including: i) caster oil/saline solution, ii) unilamellar or multilamellar liposomes, iii) biodegradable microspheres, and iv) biodegradable 3-month lasting pellets; and 2) defining the survival and immune response in animals receiving spinal injections of human neural precursors at 6 weeks to 3 months after cell grafting. In animals implanted with TAC pellets (3.4 mg/kg/day), a stable 3-month lasting plasma concentration of TAC averaging 19.1 ± 4.9 ng/ml was measured. Analysis of grafted cell survival in SOD+ or spinal trauma-injured SD rats immunosuppressed with 3-month lasting TAC pellets (3.4-5.1 mg/kg/day) showed the consistent presence of implanted human neurons with minimal or no local T-cell infiltration. These data demonstrate that the use of TAC pellets can represent an effective, long-lasting immunosuppressive drug delivery system that is safe, simple to implement and is associated with a long-term human neural precursor survival after grafting into the spinal cord of SOD+ or spinal trauma-injured SD rats.
authors.affiliation: Neuroregeneration Laboratory, Department of Anesthesiology, University of California - San Diego, La Jolla, CA, USA; Institute of Biology and Ecology, Faculty of Science, P.J. Safarik University, Moyzes street 11, 040 01 Kosice, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Sevc
authors.forename: Danielle
authors.initials: D
authors.lastname: Goldberg
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Gorp
authors.forename: Marjolein
authors.initials: M
authors.lastname: Leerink
authors.forename: Stefan
authors.initials: S
authors.lastname: Juhas
authors.forename: Jana
authors.initials: J
authors.lastname: Juhasova
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsala
authors.forename: Marian
authors.initials: M
authors.lastname: Hruska-Plochan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hefferan
authors.forename: Jan
authors.initials: J
authors.lastname: Motlik
authors.forename: Frantisek
authors.initials: F
authors.lastname: Rypacek
authors.forename: Ludka
authors.initials: L
authors.lastname: Machova
authors.forename: Osamu
authors.initials: O
authors.lastname: Kakinohana
authors.forename: Camila
authors.initials: C
authors.lastname: Santucci
authors.forename: Karl
authors.initials: K
authors.lastname: Johe
authors.forename: Nadezda
authors.initials: N
authors.lastname: Lukacova
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.forename: Martin
authors.initials: M
authors.lastname: Marsala
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004343:Drug Implants; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D058953:Neural Stem Cells / Q000276:immunology / Q000637:transplantation*; D009474:Neurons / Q000276:immunology / Q000637:transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology; D013119:Spinal Cord Injuries / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D004343:Drug Implants; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: Human neural precursors; Immunosuppression; Spinal grafting; Sprague–Dawley rat; T-lymphocyte; Tacrolimus pellet; Xenograft