Down-regulation of interleukin-2 and interferon-gamma and maintenance of interleukin-4 and interleukin-10 production after administration of an anti-CD3 monoclonal antibody in mice.
BACKGROUND
Activating anti-CD3 monoclonal antibodies (mAbs), such as OKT3, are potent immunosuppressive agents that are widely used in clinical transplantation. We investigated whether the in vivo induction of T cell unresponsiveness contributes to the immunosuppressive properties of the anti-mouse-CD3 mAb 145-2C11.


METHODS
After a single in vivo administration of 145-2C11 residual T cells were restimulated in vivo and in vitro to assess cytokine production. Mice were also transplanted with allogeneic skin 9 days after 145-2C11 administration to investigate whether the immunosuppressive properties of the antibody persist after the reexpression of the T cell receptor.


RESULTS
Pretreatment with anti-CD3 mAbs caused a profound deficit in both interleukin- (IL) 2 and interferon- (IFN) y secretion upon restimulation in vivo, whereas IL-4 was only partially inhibited and IL-10 production was significantly increased. Purified T cells obtained from mice injected with anti-CD3 mAb also displayed deficient IL-2 and IFN-gamma production together with persisting IL-4 and IL-10 secretion. 145-2C11 had immunosuppressive properties that per sisted after the reexpression of the T cell receptor because mice transplanted with allogeneic skin 9 days after a single anti-CD3 mAb injection still had significantly prolonged graft survival (14.1+/-0.6 days vs. 10.7+/-0.4 days in controls, P<0.02). Blocking IL-4 and IL-10 by neutralizing mAbs further prolonged skin graft survival in mice injected with 145-2C11 (18.3+/-0.7 vs. 14.8+/-0.6 days, P<0.02).


CONCLUSIONS
The in vivo administration of the 145-2C11 anti-CD3 mAb results in the selective inhibition of Thl-type cytokine secretion upon restimulation, which correlates with a state of immunosuppression. The persistent production of Th2-type cytokines does not contribute to the anti-CD3 mAb-mediated prolonged survival of skin allografts in our experimental model.
Wissing
K M
KM
Département de Néphrologie, Hôpital Erasme, Brussels, Belgium.
Desalle
F
F
Abramowicz
D
D
Willems
F
F
Leo
O
O
Goldman
M
M
Alegre
M L
ML
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000378:metabolism*; D015847:Interleukin-4 / Q000096:biosynthesis*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016038:Skin Transplantation; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma