Long-term survival of xenogeneic heart grafts achieved by costimulatory blockade and transient mixed chimerism.
BACKGROUND
Xenotransplantation holds great promise in clinical medicine, but is limited by the vigorous rejection response elicited against solid organs transplanted across species barriers. In this study, we investigated the role of anti-CD40L monoclonal antibody (mAb) in inducing xenogeneic mixed chimerism and donor-specific heart transplantation tolerance.


METHODS
One day before heart transplantation, mice were injected intraperitoneally with anti-mouse CD8/NK1.1/Thy1.2 mAbs. On day 0, the mice received 3 Gy total body irradiation (TBI), an intravenous injection of unseparated bone marrow (BM) harvested from F344 rats, and an intraperitoneal injection of hamster antimouse CD40L mAb, MR1. Heart grafts from F344 rats were heterotopically transplanted into the abdomen of B6 mouse recipients. Using flow cytometric analysis of peripheral white blood cells, we assessed donor hematopoiesis at various times after bone marrow transplantation (BMT).


RESULTS
Chimerism subsided gradually and disappeared completely 18 weeks after BMT. The cardiac graft survived permanently, even after the mixed chimerism disappeared. To determine if the mice acquired donor-specific tolerance, second rat heart grafts were transplanted 120 days after the first heart transplantation. The second transplanted hearts were also accepted over 60 days. Histological analysis revealed no remarkable vasculopathy in the coronary vessels at any stage.


CONCLUSIONS
These findings clearly show that costimulatory blockade plays an important role in inducing xenochimerism, and that transient mixed chimerism can induce permanent acceptance of rat to mouse cardiac xenografts. Transplantation of xenogeneic bone marrow cells under costimulatory blockade at the time of heart transplantation may induce transplantation tolerance.
Murakami
Masanori
M
Department of Surgery and Clinical Science, Yamaguchi University, Graduate School of Medicine, Japan.
Ito
Hiroshi
H
Harada
Eijiro
E
Enoki
Tadahiko
T
Sykes
Megan
M
Hamano
Kimikazu
K
D000818:Animals; D016026:Bone Marrow Transplantation / Q000502:physiology; D005260:Female; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation / Q000502:physiology*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D012086:Reoperation; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous / Q000502:physiology*