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
Wissing, K.M.; Desalle, F.; Abramowicz, D.; Willems, F.; Leo, O.; Goldman, M.; Alegre, M.L.
Transplantation 68(5): 677-684
1999
ISSN/ISBN: 0041-1337 PMID: 10507488 Document Number: 506990
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) gamma 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 persisted 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). Conclusion. The in vivo administration of the 145-2C11 anti-CD3 mAb results in the selective inhibition of Th1-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.