Cyclosporine inhibits long-term survival in cardiac allografts treated with monoclonal antibody against CD45RB.
BACKGROUND
We have previously reported that a monoclonal antibody to CD45RB is a novel immunosuppressive agent; however, the optimal regimen in cardiac allografts remains unknown. The present study was undertaken to determine the optimal protocol of this therapy and its interaction with cyclosporine.


METHODS
A heterotopic heart allograft model was used in C57BL/6 to BALB/c mice. The following studies were conducted: 1) dose response study (low, intermediate, and high doses at 1, 3, and 9 mg/kg/day respectively), 2) short course (2 days) therapy vs. long course (9 days) therapy, 3) pretreatment (starting on day -1) vs no pretreatment, 4) daily therapy vs. alternative day therapy, and 5) monoclonal antibody treatment with and without cyclosporine.


RESULTS
The efficacy of the CD45RB monoclonal antibody was dose and duration dependent (p<0.01). Pretreatment significantly improved the efficacy of this therapy (74.5+/-13.4 days vs. 30.6+/-1.5 days, p<0.01). Daily therapy was superior to alternate day therapy (74.5+/-13.4 days vs. 30.4+/-1.5 days, p<0.03). Interestingly, we found that administration of cyclosporine prior to, at the same time as, or after administration of the CD45RB monoclonal antibody had a detrimental effect on graft survival compared to mAb treated alone (16.6+/-0.4 days, 25+/-2.3 days, and 35.3+/-0.9 days respectively vs. 74.5 days, p<0.01).


CONCLUSIONS
Immunosuppression with CD45RB monoclonal antibody is dose and duration dependent. Pretreatment and daily therapy improves results. Addition of cyclosporine inhibits long-term graft survival achieved by the monoclonal antibody alone.
Parry
N
N
Department of Surgery, The University of Western Ontario, London, Canada.
Lazarovits
A I
AI
Wang
J
J
Garcia
B
B
Luke
P
P
Poppema
S
S
Zhong
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D017493:Leukocyte Common Antigens