Treatment of cardiac allografts with established leukocyte infiltration by modulation of alpha4 (CD49d) and leukocyte function-associated antigen-1 (CD11a/CD18) integrin function.
BACKGROUND
Leukocyte infiltration is a landmark feature of organ rejection. The present study was undertaken to determine whether monoclonal antibodies (mAb) against alpha4 (CD49d) and/or leukocyte function-associated antigen-1 (LFA-1; CD11a/CD18) would reverse ongoing rejection in a mouse C57BL/6-to-BALB/c heart transplant model.


METHODS
Control animals had rejection on postoperative day (POD) 8. Treatment with mAb started on POD 4 when leukocyte infiltration was well established. The recipients were treated with (1) mAb LFA-1, (2) mAb alpha4, and (3) mAbs LFA-1 + alpha4 at a dose of 6 mg/kg/day i.v. on PODs 4, 5, and 7. Untreated and rat IgG-treated animals were used as controls.


RESULTS
Control animals experienced rejection on POD 8. Treatment with mAb against LFA-1 or alpha4 alone prolonged allograft survival to 17.0+/-3.2 and 24.3+/-4.6 days, respectively (P < 0.01 vs. controls). Combination therapy with both mAb increased allograft survival to 28.2+/-3.7 days (P < 0.01 vs. controls). Sequential pathological studies showed the mAb to alpha4, but not LFA-1, markedly reduced the degree of lymphocytic infiltration in cardiac allografts. In contrast, a different pattern was observed using in vitro studies: mAb to LFA-1, not alpha4, significantly reduced proliferative responses in mixed lymphocyte culture and interleukin-2 production from recipient splenocytes on POD 8.


CONCLUSIONS
These data indicate that integrins play an important role in rejection. Although the effect of mAb against alpha4 and LFA-1 may involve different mechanisms, treatment with mAbs to integrins may be valuable in future clinical transplantation by averting ongoing rejection and prolonging graft survival.
Transplantation and Immunobiology, The John P. Robarts Research Institute, London, Ontario, Canada.
B M
BM
Chan
H
H
Zheng
H
H
Wang
S
S
Uniyal
B
B
Garcia
J
J
Wang
R
R
Zhong
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D039441:Integrin alpha4; D016023:Integrins / Q000502:physiology; D007964:Leukocytosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D051381:Rats
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D039441:Integrin alpha4