TREATMENT OF CARDIAC ALLOGRAFTS WITH ESTABLISHED LEUKOCYTE INFILTRATION BY MODULATION OF ALPHA-4 (CD49D) AND LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 (CD11A CD18) INTEGRIN FUNCTION/

Background Leukocyte infiltration is a landmark feature of organ rejec tion. The present study was undertaken to determine whether monoclonal antibodies (mAb) against alpha 4 (CD49d) and/or leukocyte function-as sociated 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 mA b started on POD 4 when leukocyte infiltration was well established, T he recipients were treated with (1) mAb LFA-1, (2) m4b alpha 4, and (3 ) mAbs LFA-1 + alpha 4 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. Resul ts. Control animals experienced rejection on POD 8, Treatment with mAb against LFA-1 or alpha 4 alone prolonged allograft survival to 17.0+/ -3.2 and 24.3+/-4.6 days, respectively (P<0.01 vs. controls). Combinat ion therapy with both mAb increased allograft survival to 28.2+/-3.7 d ays (P<0.01 vs. controls). Sequential pathological studies showed the mAb to alpha 4, but not LFA-1, markedly reduced the degree of lymphocy tic infiltration in cardiac allografts, In contrast, a different patte rn was observed using in vitro studies: mAb to LFA-1, not alpha 4, sig nificantly reduced proliferative responses in mixed lymphocyte culture and interleukin-2 production from recipient splenocytes on POD 8. Con clusion. These data indicate that integrins play an important role in rejection. Although the effect of mAb against alpha 4 and LFA-1 may in volve different mechanisms, treatment with mAbs to integrins may be va luable in future clinical transplantation by averting ongoing rejectio n and prolonging graft survival.