Anti-CD3 monoclonal antibodies are largely used as therapeutic agents in clinical transplantation. Constrating with their potent immunosuppressive activity anti-CD3 antibodies also transiently express T cell activating properties. In vitro they promote T cell mitogenesis and in vivo, the self-limited cytokine release (including TNF, IFN gamma, IL-2, IL-3, IL-6) observed following the first anti-CD3 injection, is responsible for an acute clinical syndrome. Clinical studies as well as the experimental data obtained in mice, confirmed that TNF plays a fundamental role in the anti-CD3 induced syndrome. The administration of anti-TNF monoclonal antibodies prior to the first anti-CD3 injection prevents the syndrome not only by blocking TNF bioactivity but also, by modulating the circulating levels of the other anti-CD3-induced cytokins. In particular, this model allowed the description of regulatory pathways existing between TNF and IFN gamma, which in turn regulate IL-3 and IL-6 release.