Long-term donor-specific tolerance in rat cardiac allografts by intrabone marrow injection of donor bone marrow cells.
BACKGROUND
Donor-specific central tolerance in cardiac allograft can be induced by hematopoietic chimerism via conventional intravenous bone marrow transplantation (IV-BMT). However, there are problems with IV-BMT, such as the risk of graft failure and of the toxicity from conditioning regimens.


METHODS
A new method for heart transplantation is presented. This method consists of administration of fludarabine phosphate (50 mg/kg) and fractionated low-dose irradiation (3.5 Gyx2 or 4.0 Gyx2), followed by intrabone marrow injection of whole bone marrow cells (IBM-BMT) plus heterotopic heart transplantation.


RESULTS
Cardiac allografts with IBM-BMT were accepted and survived long-term (>10 months) showing neither acute rejection nor chronic rejection including cardiac allograft vasculopathy by such conditioning regimens. In contrast, cardiac allografts with conventional IV-BMT were rejected within 1 month after the treatment with irradiation of 3.5 Gyx2 or within 3 months after the treatment with irradiation of 4.0 Gyx2. Macrochimerism (>70%) was favorably established and stably maintained by IBM-BMT but not IV-BMT. Low levels of transient mixed chimerism (<7%) were induced by IV-BMT with fludarabine plus 4.0 Gyx2, but the chimerism was lost within 1 month after the treatment.


CONCLUSIONS
These findings indicate that IBM-BMT is a feasible strategy for the induction of persistent donor-specific tolerance, enables the use of reduced radiation doses as conditioning regimens, and obviates the need for immunosuppressants.
Guo
Kequan
K
First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan.
Inaba
Muneo
M
Li
Ming
M
An
Jun
J
Cui
Wenhao
W
Song
Changye
C
Wang
Jianfeng
J
Cui
Yunze
Y
Sakaguchi
Yutaku
Y
Tsuda
Masanobu
M
Omae
Mariko
M
Ando
Yugo
Y
Li
Qing
Q
Wang
Xiaoli
X
Feng
Wei
W
Ikehara
Susumu
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000379:methods*; D046528:Chimerism; D004307:Dose-Response Relationship, Radiation; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007267:Injections; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D013997:Time Factors; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000970:Antineoplastic Agents; D014740:Vidarabine; C024352:fludarabine