Mechanisms involved in ADCC

The mechanisms involved in ADCC are still not well defined. As mentioned above, the cytotoxic response is triggered by the cross-linking of FcR expressed by the effector cells, which is induced by antibodies that coat target cells. It is also well established that cytotoxicity does not involve the participation of a diffusible cytotoxic factor. In fact, when mixtures of antibody-coated and uncoated target cells are incubated together with effector cells, lysis of non-sensitized targets is not observed.

• Different metabolic requirements are involved in the induction of ADCC, depending not only on the nature of the effector cells but also on their activation state, the properties of antibodies and the nature of target cells. The role of Ca2+ in the induction of ADCC appears to differ for distinct effector cells. It is well known that the stimulation of human neutrophils and monocytes with immune complexes triggers Ca2+ mobilization. The increase in [Ca2+]; appears to play an important role in neutrophil-mediated ADCC; however, it represents a secondary phenomenon in monocyte-mediated ADCC. Studies performed to evaluate the role of the cytoskeleton have also demonstrated major differences between neutrophils and monocytes. Thus, integrity of microfilament and microtubule systems is required for neutrophil-mediated ADCC, but it plays no role in cytotoxicity performed by monocytes.

The cytolytic mechanisms responsible for target cell destruction also seem to be quite different in distinct ADCC models. The generation of reactive oxygen intermediates (ROI), such as superoxide anion and hydrogen peroxide, plays a major role in some models of phagocytic cell-mediated ADCC. By contrast, ROI are not involved in cytotoxicity performed by lymphoid cells, which appears to be dependent on nonoxidative mechanisms, including the release of cytoplasmic granules containing perforin and gran-zymes. Furthermore, employing monocytes from chronic granulomatous disease patients, which generate very limited amounts of ROI, it was found that oxidative mechanisms play an important role in ADCC mediated by monocytes against red blood cells but not against lymphoblastoid cells. Interestingly, these data indicate that a single type of effector cell is able to perform ADCC towards different target cells via distinct cytolytic mechanisms.

It is possible that many of the variables observed in different models of ADCC may result from the participation of distinct types of FcyR in the induction of cytotoxicity. In this regard, it is noteworthy that FcyR share structurally related ligand-binding domains, but differ in their transmembrane and intracellular domains which mediate intracellular signaling.

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