Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
BACKGROUND
Establishment of hematopoietic chimerism is the most stable strategy for donor-specific tolerance. Safer pretreatment regimens are needed for clinical application. We evaluated the efficacy of a simple protocol using cyclophosphamide (CYP) on induction of chimerism and organ transplant tolerance across major histocompatibility complex (MHC) barriers in the rat.


METHODS
Bone marrow cells from BN (RT1(n)) donors were infused to LEW (RT1(l)) recipients on day 0 after a single injection of CYP at various doses on day -1. Donor-derived hematopoietic chimerism was evaluated by flowcytometry. The recipients received BN or third party (BUF) heart allografts on day 100.


RESULTS
While pretreatment with 200 mg/kg of CYP induced high levels of hematopoietic chimerism, six of eight recipients died of severe graft-versus-host-disease (GVHD). CYP at dose of 150 mg/kg induced 36.5 +/- 24.1% of donor-derived chimerism on day 10, and sustained macrochimerism was seen until day 100 without GVHD. Pretreatment with 100 mg/kg of CYP resulted in only transient chimerism (4.8 +/- 5.2%) which disappeared by day 20. In the recipients with 50 mg/kg of CYP, donor bone marrow cells were rapidly rejected and no chimerism was observed. The recipients with 150 mg/kg of CYP accepted BN heart allografts (>100 days x 5), while rejecting BUF allografts by day 12 (n = 4). BN heart allografts were rejected in the recipients with 100 (MST: 57 days, n = 5) and 50 mg/kg (MST: 7 days, n = 5) of CYP.


CONCLUSIONS
A single dose of CYP can induce hematopoietic chimerism across MHC-barriers. The dose of 150 mg/kg seems to be optimal to induce organ transplant tolerance without developing GVHD.
Okayama
Junji
J
First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
Ko
Saiho
S
Kanehiro
Hiromichi
H
Kanokogi
Hideki
H
Hisanaga
Michiyoshi
M
Ohashi
Kazuo
K
Sho
Masayuki
M
Nagao
Mitsuo
M
Ikeda
Naoya
N
Kanamura
Tetsuhiro
T
Akashi
Satoru
S
Nakajima
Yoshiyuki
Y
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology*; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide