Antibodydependent Cellular Cytotoxicity

Jorge Raúl Geffner, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

It was first shown by Moller in 1965 that a wide variety of target cells, coated with low amounts of specific immunoglobulin G (IgG) antibodies, can be lysed in vitro by lymphocytes not previously sensitized to target cell antigens. Further studies established that nonlymphoid cells such as polymorphonuclear leukocytes, monocytes and macrophages can also mediate this cytotoxic mechanism, known as antibody-dependent cellular (or cell-mediated) cytotoxicity (ADCC). The ability of a given effector cell population to perform this response, however, appears to be strongly dependent on several factors. They include the nature of the target cells, the isotype and density of antibodies coating the target cell surface, the class of receptor for the Fc portion of immunoglobulin molecule (FcR) involved, and the activation state of effector cells. In all cases, ADCC is induced without major histocompatibility complex (MHC) restriction and therefore it is operative in syngeneic, allogeneic and xenogeneic systems.

It should be noted that the specificity of ADCC is conferred by antibodies, which at extremely low concentrations, far below those required for complement-mediated lysis, are able to induce cytotoxicity. In fact, target cells coated with as few as 100500 immunoglobulin molecules can be destroyed through ADCC.

Although the mechanisms involved in ADCC are still not completely understood, it is well established that ADCC is triggered by the interaction of target cell-bound IgG antibodies with the receptors for the Fc fragment of IgG (FcyR) expressed on the effector cells. These receptors, which act as signal-transducing molecules, are all members of the immunoglob-ulin-like superfamily of membrane receptors. They are expressed by human hematopoietic cells, including natural killer (NK), B and T lymphocytes, as well as by monocytes, macrophages, polymorphonuclear leukocytes, mast cells and platelets. Most of them express multiple types of FcyR, which fall into three main classes based on structural analysis of the genes and proteins for these receptors: the high affinity FcyRI (CD64), the low affinity FcyRII (CD32) and the low/intermediate affinity FCyRIII (CD16), which involve at least 12 different isoforms.

FcyR mediate a wide array of responses. They range from effector functions, such as ADCC, phago cytosis, pinocytosis and release of inflammatory mediators, to immunoregulatory signals, such as modulating antigen presentation, lymphocyte proliferation and antibody production. Triggering of biological responses through FcyR normally requires cross-linking of these receptors, which is usually induced by IgG immune complexes.

ADCC has been defined and characterized in several experimental models performed in vitro. Although its relevance in vivo has not been clearly established, several lines of evidence suggest that it plays an important role in host immune defense.

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