The role of cyclophosphamide and granulocyte colony-stimulation factor in achieving high-level chimerism in allotransplanted limbs.
The establishment of a high-level of chimerism may be the most stable strategy for donor-specific tolerance. The purpose of this study was to evaluate the efficacy of a new protocol using cyclophosphamide (CYP) and granulocyte colony-stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. Seventy-three whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. CYP was injected at day 2, and G-CSF was given from day 0 to 3. Nontreated limb allografts were rejected after 4.2 days. In FK506-treated group for 28 days, the survival time was prolonged to 64 days. In the group treated with CYP/G-CSF, limb allografts were rejected after 5.4 days and 5 of 15 recipients showed acute lethal graft-versus-host disease (GVHD). Polymerase chain reaction (PCR) study showed a high level of chimerism even within 1 week after transplantation. Fourteen of 30 recipients given CYP/G-CSF/FK506 died within 2 weeks. The limb survival was significantly prolonged, however, with three grafts surviving more than 300 days. Seven recipients (24%) showed chronic GVHD. A high-level of chimerism was maintained when limb allografts were not rejected by recipients. Limb allografting could function as a vascularized carrier for bone marrow transplantation, provide a continuous source of donor cells and contribute to a high level of chimerism in the recipient. Pretransplant CYP followed by G-CSF and FK506 treatment significantly prolonged the survival of limb allografts but frequently caused chronic GVHD in the recipients.
Muramatsu
Keiichi
K
Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. muramatu@po.cc.yamaguchi-u.ac.jp
You-Xin
Song
S
Hashimoto
Takahiro
T
Matsunaga
Tsunemitsu
T
Taguchi
Toshihiko
T
D000818:Animals; D030801:Animals, Genetically Modified; D046528:Chimerism / Q000187:drug effects*; D003520:Cyclophosphamide / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005121:Extremities / Q000637:transplantation; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology; D016378:Tissue Transplantation; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D016559:Tacrolimus