NONDEPLETING ANTI-CD4 ANTIBODIES IN TRANSPLANTATION - EVIDENCE THAT MODULATION IS FAR LESS EFFECTIVE THAN PROLONGED CD4 BLOCKADE

CD4(+) T cells are obvious targets for immunotherapy since they appear to be pivotal in rejection responses. Current interest in clinical tr ansplantation is focused on the potential use of nondepleting anti-CD4 antibodies largely because depletion of CD4(+) T cells may lead to pr olonged periods of nonspecific immunosuppression. We have examined the efficacy of two nondepleting antibodies, KT6 and YTS 177.9, in a mous e cardiac allograft model. KT6 causes abrupt and prolonged occupation of CD4 molecules in vivo, while YTS 177.9 results in rapid and almost complete modulation of CD4 from the cell surface. In identical periope rative two-dose protocols, equivalent doses of KT6 were more effective than YTS 177.9 (MST 58 days and 24 days, respectively). When the trea tment protocols were redesigned to include one or two additional doses of antibody, given as CD4 molecules were either released from blockad e (KT6) or re-expressed following modulation (YTS177.9), the YTS 177.9 protocol led only to a slight improvement in graft survival (MST 51 d ays), whereas the modified KT6 regimen gave indefinite survival in 100 % of the recipients. These data clearly show that modulating anti-CD4 antibodies may be far less effective than antibodies that effect prolo nged CD4 occupation, a significant observation especially in relation to the proposed clinical use of the antibody OKT4A, which appears to c ause modulation rather than CD4 blockade.