TY - JOUR
T1 - Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival
AU - Sevc, Juraj
AU - Goldberg, Danielle
AU - Van Gorp, Sebastiaan
AU - Leerink, Marjolein
AU - Juhas, Stefan
AU - Juhasova, Jana
AU - Marsala, Silvia
AU - Hruska-Plochan, Marian
AU - Hefferan, Michael P.
AU - Motlik, Jan
AU - Rypacek, Frantisek
AU - Machova, Ludka
AU - Kakinohana, Osamu
AU - Santucci, Camila
AU - Johe, Karl
AU - Lukacova, Nadezda
AU - Yamada, Kazuhiko
AU - Bui, Jack D.
AU - Marsala, Martin
PY - 2013/10
Y1 - 2013/10
N2 - 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. Published by Elsevier Inc.
AB - 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. Published by Elsevier Inc.
KW - Immunosuppression
KW - Xenograft
KW - Human neural precursors
KW - Spinal grafting
KW - Sprague-Dawley rat
KW - T-lymphocyte
KW - Tacrolimus pellet
U2 - 10.1016/j.expneurol.2013.05.017
DO - 10.1016/j.expneurol.2013.05.017
M3 - Article
C2 - 23748136
SN - 0014-4886
VL - 248
SP - 85
EP - 99
JO - Experimental Neurology
JF - Experimental Neurology
ER -