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 transplantation is focused on the potential use of nondepleting anti-CD4 antibodies largely because depletion of CD4+ T cells may lead to prolonged periods of nonspecific immunosuppression. We have examined the efficacy of two nondepleting antibodies, KT6 and YTS 177.9, in a mouse 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 perioperative two-dose protocols, equivalent doses of KT6 were more effective than YTS 177.9 (MST 58 days and 24 days, respectively). When the treatment protocols were redesigned to include one or two additional doses of antibody, given as CD4 molecules were either released from blockade (KT6) or re-expressed following modulation (YTS177.9), the YTS 177.9 protocol led only to a slight improvement in graft survival (MST 51 days), 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 prolonged CD4 occupation, a significant observation especially in relation to the proposed clinical use of the antibody OKT4A, which appears to cause modulation rather than CD4 blockade.
Darby
C R
CR
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, United Kingdom.
Bushell
A
A
Morris
P J
PJ
Wood
K J
KJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016525:Antigenic Modulation; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens