Long-term limb allograft survival using a short course of anti-CD45RB monoclonal antibody, LF 15-0195, and rapamycin in a mouse model.
BACKGROUND
The purpose of this study was to determine if a short course of monoclonal antibody (mAb) against CD45RB, LF 15-0195, and rapamycin would achieve long-term survival by inducing tolerance in a mouse limb transplant model.


METHODS
Group 1 (n=9) consisted of nine isogenic (C57BL/6) transplants. Group 2 (n=3) included C57BL/6-to-BALB/c transplants receiving no drug therapy. Group 3 mice (n=4) were treated with mAb (3 mg/kg) and LF (2 mg/kg), and Group 4 (n=13) was treated with mAb, LF, and rapamycin (2 mg/kg). Both treatment groups received drug treatment for only 14 days posttransplantation. Animals were sacrificed if they displayed evidence of rejection or when deemed to be tolerant (defined as >day 100).


RESULTS
All isografts had normal histology and graft function on day 100. Untreated C57BL/6-to-BALB/c allografts developed acute rejection within 10 days. The combination of mAb and LF prolonged allograft survival to a mean of 39+/-7 days. In Group 4, two animals had to be sacrificed at days 28 and 76 due to acute urinary retention. Transplant tolerance was achieved in 8 of the remaining 11 animals with a mean survival time of 100+/-12 days. Donor specific tolerance was demonstrated through permanent acceptance of skin grafts from the donor strain and rejection of skin grafts from C3H mice. Three Group 4 animals showed clinical and histological signs of mild, chronic rejection. Dendritic cells isolated from tolerant recipients exerted a suppressive effect in mixed lymphocyte reaction.


CONCLUSIONS
A short course of anti-CD45RB mAb and LF 15-0195 prolonged limb allograft survival. The addition of rapamycin induced limb allograft tolerance which is associated with the generation of tolerogenic dendritic cells that suppressed T-cell proliferation.
Zhong
Toni
T
Division of Plastic Surgery, Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
Liu
Yuanqing
Y
Jiang
Jifu
J
Wang
Hao
H
Temple
Claire L F
CL
Sun
Hongtao
H
Garcia
Bertha
B
Zhong
Robert
R
Ross
Douglas C
DC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D005121:Extremities / Q000637:transplantation*; D006085:Graft Survival / Q000502:physiology*; D006146:Guanidines / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D020123:Sirolimus / Q000627:therapeutic use*; D016038:Skin Transplantation / Q000276:immunology*; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology*
D000911:Antibodies, Monoclonal; D006146:Guanidines; D007166:Immunosuppressive Agents; D007518:Isoantibodies; C434185:LF 150195; D017493:Leukocyte Common Antigens; D020123:Sirolimus