Anti-CD3 F(ab')2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb.
The use of anti-CD3 monoclonal antibodies to treat organ allograft rejection has been complicated by (1) the morbidity associated with the initial dose, (2) the humoral response of the patients against the mAbs, and (3) the generalized immunosuppression induced by the mAbs. We investigated the potential of F(ab')2 fragments of the anti-murine-CD3 mAb, 145-2C11, to avoid these complications in the murine model. Both whole mAb and F(ab')2 fragments induced T cell depletion. However, injection of F(ab')2 fragments of anti-CD3 mAb did not cause T cell activation, and did not induce the morbidity and mortality observed following injection of whole mAb. The humoral response against the F(ab')2 fragments was significantly reduced compared with the response against the whole mAb. Furthermore, repeated administration of F(ab')2 fragments of anti-CD3 mAb resulted in prolongation of allogeneic skin graft survival superior to that seen following treatment with a single dose of whole mAb. Finally, while T cells from mice treated with whole mAb displayed profound suppression of in vitro CTL generation, T cells from mice treated with F(ab')2 fragments had significant in vitro CTL function. These results suggest that the use of F(ab')2 fragments of anti-CD3 mAb may offer significant advantages over whole mAb for the induction and maintenance of immunosuppression.
Hirsch
R
R
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Bluestone
J A
JA
DeNenno
L
L
Gress
R E
RE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D006084:Graft Rejection / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology* / Q000302:isolation & purification; D007166:Immunosuppressive Agents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell