Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival

Juraj Sevc, Danielle Goldberg, Sebastiaan Van Gorp, Marjolein Leerink, Stefan Juhas, Jana Juhasova, Silvia Marsala, Marian Hruska-Plochan, Michael P. Hefferan, Jan Motlik, Frantisek Rypacek, Ludka Machova, Osamu Kakinohana, Camila Santucci, Karl Johe, Nadezda Lukacova, Kazuhiko Yamada, Jack D. Bui, Martin Marsala*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Web of Science)

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. Published by Elsevier Inc.
Original languageEnglish
Pages (from-to)85-99
JournalExperimental Neurology
Volume248
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Immunosuppression
  • Xenograft
  • Human neural precursors
  • Spinal grafting
  • Sprague-Dawley rat
  • T-lymphocyte
  • Tacrolimus pellet

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