Heart allograft tolerance without development of posttransplant cardiac allograft vasculopathy in chimerism-based, drug-induced tolerance.
BACKGROUND
Recently, we have described a drug (cyclophosphamide [CP] plus busulfan [BU])-induced skin allograft tolerance in mice that can regularly overcome fully H-2-mismatched barriers. Using this method, we have investigated whether or not this regimen can prolong the survival of heart allografts and inhibit the development of posttransplant cardiac allograft vasculopathy (CAV).


METHODS
The components of the method are intravenous administration of 1 x 108 allogeneic spleen cells on day 0, intraperitoneal injection of 200 mg/kg of CP and 30 mg/kg of BU on day 2, and intravenous injection of T cell-depleted 1 x 107 allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting was performed on day 28. Chimerism in peripheral blood was followed by flow cytometric analysis, and histological analysis was performed at various times after grafting.


RESULTS
In a fully major histocompatability complex (MHC)-mismatched combination of B10.D2 (H-2d, IE+)-->B10 (H-2b, IE-), stable, multilineage-mixed chimerism was observed permanently. B10.D2 heart grafts were accepted permanently in a donor-specific manner, and posttransplant CAV did not develop.


CONCLUSIONS
These results demonstrated that the drug-induced tolerance recently established by us can regularly induce a long-lasting heart allograft tolerance without development of CAV.
Zhang
Qi-Wei
QW
Department of Cardiovascular Surgery, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Tomita
Yukihiro
Y
Matsuzaki
Goro
G
Shimizu
Ichiro
I
Iwai
Toshiro
T
Okano
Shinji
S
Minagawa
Ryosuke
R
Nakashima
Yutaka
Y
Sueishi
Katsuo
K
Nomoto
Kikuo
K
Yasui
Hisataka
H
D000818:Animals; D002066:Busulfan / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D006650:Histocompatibility Testing; D007108:Immune Tolerance; D016130:Immunophenotyping; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan