Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys

被引:144
作者
Kimikawa, M
Sachs, DH
Colvin, RB
Bartholomew, A
Kawai, T
Cosimi, AB
机构
[1] MASSACHUSETTS GEN HOSP,DEPT SURG,TRANSPLANTAT UNIT,GEN SURG SERV,BOSTON,MA 02114
[2] MASSACHUSETTS GEN HOSP,TRANSPLANTAT BIOL RES CTR,BOSTON,MA 02114
[3] HARVARD UNIV,SCH MED,DEPT PATHOL,BOSTON,MA 02114
[4] TOKYO WOMENS MED COLL,DEPT SURG,TOKYO 162,JAPAN
关键词
D O I
10.1097/00007890-199709150-00008
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. We demonstrated previously that a nonmyeloablative preparative regimen can induce mixed chimerism and allograft tolerance in cynomolgus monkeys. Methods. The current studies were designed to clarify the importance and toxicity of various elements of the allotolerance conditioning regimen by: fractionating or reducing the whole-body irradiation (WBI) dosage; adding deoxyspergualine; or deleting donor bone marrow, cyclosporine, irradiation, or splenectomy. Results. Monkeys treated without donor bone marrow, cyclosporine, or irradiation did not develop chimerism or long-term allograft survival. One of three monkeys treated without splenectomy developed chimerism but died of a surgical complication. The other two did not develop chimerism and rejected by day 117. Six of six monkeys treated with 300 cGy of fractionated WBI developed chimerism. Five of these recipients had long-term graft survival. Only two of four monkeys treated with 250 cGy developed chimerism, so a a-week course of deoxyspergualine was added. This led to chimerism in two monkeys, but one died of ureteral stenosis and the other died of allograft rejection. An unanticipated high incidence of ureteral complications felt to be secondary to rejection episodes and ischemic injury was observed in the long-term surviving animals. Conclusions. All parameters of the original preparative regimen seem to be essential for consistent success. The degree of lymphocyte depletion was proportional to the WBI dose. Long-term graft survival was observed only in recipients achieving lymphocyte chimerism of >1.5%. In this model, lymphocyte depletion seems to be the best predictor of chimerism, and significant lymphocyte chimerism seems to be important in achieving tolerance.
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页码:709 / 716
页数:8
相关论文
共 20 条
[1]  
CECKA JM, 1994, CLIN TRANSPLANT, V8, P324
[2]  
COSIMI AB, 1990, SURGERY, V108, P406
[3]  
DREIKORN K, 1975, European Urology, V1, P170
[4]  
HELLING TS, 1982, TRANSPLANT P, V14, P751
[5]   RECONSTITUTION WITH SYNGENEIC PLUS ALLOGENEIC OR XENOGENEIC BONE-MARROW LEADS TO SPECIFIC ACCEPTANCE OF ALLOGRAFTS OR XENOGRAFTS [J].
ILDSTAD, ST ;
SACHS, DH .
NATURE, 1984, 307 (5947) :168-170
[6]   MIXED ALLOGENEIC CHIMERISM AND RENAL-ALLOGRAFT TOLERANCE IN CYNOMOLGUS MONKEYS [J].
KAWAI, T ;
COSIMI, AB ;
COLVIN, RB ;
POWELSON, J ;
EASON, J ;
KOZLOWSKI, T ;
SYKES, M ;
MONROY, R ;
TANAKA, M ;
SACHS, DH .
TRANSPLANTATION, 1995, 59 (02) :256-262
[7]   INCIDENCE, DIAGNOSIS, AND TREATMENT OF URETERAL STENOSIS IN 1298 RENAL-TRANSPLANT PATIENTS [J].
KELLER, H ;
NOLDGE, G ;
WILMS, H ;
KIRSTE, G .
TRANSPLANT INTERNATIONAL, 1994, 7 (04) :253-257
[8]   URETERAL STENOSIS AFTER KIDNEY-TRANSPLANTATION - TRUE INCIDENCE AND LONG-TERM FOLLOW-UP AFTER SURGICAL-CORRECTION [J].
KINNAERT, P ;
HALL, M ;
JANSSEN, F ;
VEREERSTRAETEN, P ;
TOUSSAINT, C ;
VANGEERTRUYDEN, J .
JOURNAL OF UROLOGY, 1985, 133 (01) :17-20
[9]  
KLINTMALM GB, 1994, NEW ENGL J MED, V331, P1110
[10]   CLASSICAL TRANSPLANTATION TOLERANCE IN THE ADULT - THE INTERACTION BETWEEN MYELOABLATION AND IMMUNOSUPPRESSION [J].
LEONG, LYW ;
QIN, SX ;
COBBOLD, SP ;
WALDMANN, H .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1992, 22 (11) :2825-2830