Prevention of the humoral response induced by an anti-CD3 monoclonal antibody by deoxyspergualin in a murine model.
Multiple treatments with the potent immunosuppressant murine antihuman CD3 mAb OKT3 is sometimes precluded by the onset of a neutralizing humoral response mostly consisting of anti-idiotypic antibodies. A hamster antimurine CD3 monoclonal Ab, 145-2C11, shares many properties with OKT3, in particular the ability to induce a strong Ab response in mice. Deoxyspergulain (DSG), a metabolite of the antibiotic spergualin, has been shown to reduce Ab production triggered by pathogens in a variety of infectious models and against common antigens. In this study, we examined the ability of DSG to inhibit the humoral response induced by 145-2C11. DSG prevented the Ab production triggered by the anti-CD3 mAb in an Ag-specific manner and significantly reduced the Ab production in mice previously primed with 145-2C11. We showed that DSG had a long-term effect on B cells and a transient effect on T cells. In effect, DSG was found to induce a prolonged Ag-specific unresponsiveness of B lymphocytes, and to transiently reduce the capacity of T lymphocytes to deliver help to B cells, in part by reducing IL-4 production. DSG did not reduce the immunosuppressive properties of the anti-CD3 mAb. In fact, the combination of DSG with 145-2C11 prolonged the survival of allogeneic skin grafts when compared with the administration of 145-2C11 or DSG alone. Thus, the coadministration of DSG with OKT3 may be of clinical interest to reduce the humoral response triggered by the mAb.
Department of Medicine, University of Chicago, Illnois 60637.
M L
ML
Alegre
H A
HA
Sattar
K C
KC
Herold
J
J
Smith
M A
MA
Tepper
J A
JA
Bluestone
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016853:Muromonab-CD3 / Q000494:pharmacology*; D051381:Rats; D016038:Skin Transplantation / Q000276:immunology*
D017252:CD3 Complex; D006146:Guanidines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; C037258:gusperimus