Prolonged survival of experimental extremity allografts: a new protocol with total body irradiation, granulocyte-colony stimulation factor, and FK506.
The induction of a high-level of chimerism (macrochimerism) may be the most reliable strategy for achieving donor-specific tolerance. The purpose of this study was to evaluate the efficacy of a new protocol using total-body irradiation (TBI) and granulocyte-colony stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. In this study, we investigated whether the timing of TBI influenced the period of graft survival. In total, 50 whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. TBI was performed at days 0 and 14, and G-CSF was given for 4 days after TBI. FK506 was given for 28 days after transplant. Nontreated limb allografts were rejected after 4.2 days. The survival time was prolonged to 64 days in the FK506 monotherapy group. In the group receiving TBI at day 14, limb allograft survival was significantly prolonged to 81 days. In the group receiving TBI at day 0, 26% of recipients died but in the surviving recipients the grafts survived for longer than 1 year without lethal graft-versus-host disease (GVHD). Polymerase chain reaction (PCR) analysis revealed a high level of intrabone marrow chimerism in the recipient, thus demonstrating successful induction of macrochimerism. A new protocol of pretransplant TBI followed by treatment with G-CSF and FK506 was found to induce a high level of chimerism and to significantly prolong the survival of limb allografts in recipients without lethal GVHD.
Muramatsu
Keiichi
K
Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. muramatu@yamaguchi-u.ac.jp
Kuriyama
Ryutaro
R
Kato
Hidetoyo
H
Yoshida
Yuichiro
Y
Taguchi
Toshihiko
T
D000818:Animals; D030801:Animals, Genetically Modified; D046528:Chimerism / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D006086:Graft vs Host Disease / Q000401:mortality / Q000628:therapy*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006614:Hindlimb / Q000601:surgery; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007763:Lac Operon / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D015996:Survival Rate; D016559:Tacrolimus / Q000494:pharmacology; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000187:drug effects / Q000528:radiation effects; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D007166:Immunosuppressive Agents; D016179:Granulocyte Colony-Stimulating Factor; D016559:Tacrolimus