FC RECEPTOR-BINDING OF ANTI-CD3 MONOCLONAL-ANTIBODIES IS NOT ESSENTIAL FOR IMMUNOSUPPRESSION, BUT TRIGGERS CYTOKINE-RELATED SIDE-EFFECTS

A major drawback to the use of OKT3, a mouse anti-CD3 monoclonal antib ody (mAb), as an immunosuppressive agent is the associated cytokine re lease syndrome. We used a mouse model to elucidate the properties of a nti-CD3 mAb responsible for these cytokine-related side effects. We ha ve previously demonstrated that the hamster anti-CD3 mAb 145-2C11 indu ced strong cytokine release and morbidity in vivo, whereas two rat ant i-CD3 mAb 17A2 and KT3 did not. In the current study, we show that the mitogenic capacity of soluble anti-CD3 mAb in vitro correlates with t heir induction of side effects in vivo. Mitogenesis in vitro and tumor necrosis factor-alpha (TNF-alpha) release in vivo induced by anti-CD3 mAb could be inhibited by the anti-Fc gamma R mAb 2.4G2, indicating t hat Fc gamma R binding of anti-CD3 mAb is responsible for their mitoge nic properties and for their induction of side effects. Importantly, t he two non-mitogenic rat anti-CD3 mAb were equally capable of suppress ing skin allograft rejection as the mitogenic hamster anti-CD3 mAb, su ggesting Fc gamma R binding of anti-CD3 mAb is not essential for their immunosuppressive properties. This suggestion is reinforced by our de monstration that administration of 2.4G2 in vivo did not interfere wit h immunosuppression of skin allograft rejection by 145-2C11. These fin dings suggest that clinical use of non-mitogenic anti-CD3 mAb will res ult in effective immunosuppression without cytokine-related side effec ts.