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Antibody-dependent Advanced article

Cellular Cytotoxicity . Introduction


Article Contents

(ADCC) . Fc Receptors are Trigger Molecules for ADCC

. Cellular Effectors of ADCC

. Mechanisms of Cytotoxicity
Jean-Luc Teillaud, Cordeliers Research Center, INSERM U.872, Université Paris-Descartes et
. Inhibition of Cytotoxicity
Université Pierre et Marie Curie, Paris, France
. Regulation of ADCC

. Role of ADCC in Host Immunity


Based in part on the previous version of this eLS article ‘Antibody-
dependent Cellular Cytotoxicity’ (2006) by Robert F Graziano and Paul . Summary
M Guyre.
Online posting date: 16th July 2012

Antibody-dependent cell-mediated cytotoxicity (ADCC) is ADCC is conferred by target-bound antibody and can be
the killing of an antibody-coated target cell by a cytotoxic induced in vitro by antibody concentrations well below
effector cell through a nonphagocytic process, charac- those needed to activate complement-mediated lysis.
terised by the release of the content of cytotoxic granules Receptors for the Fc region of Ig (FcR) on the plasma
or by the expression of cell death-inducing molecules.
membrane of the effector cell are necessary but not suf-
ficient for ADCC activity. Once antibody has bound to the
ADCC is triggered through interaction of target-bound
target cell, its interaction with either activating or inhibi-
antibodies (belonging to IgG or IgA or IgE classes) with tory FcR on the cytotoxic effector cell appears to dictate the
certain Fc receptors (FcRs), glycoproteins present on the precise signalling pathways that are stimulated. When
effector cell surface that bind the Fc region of immuno- target-bound antibodies crosslink activating FcR (char-
globulins (Ig). Effector cells that mediate ADCC include acterised by the presence of an immunoreceptor tyrosine-
natural killer (NK) cells, monocytes, macrophages, neu- based activating motif, ITAM, in their intracellular (IC)
trophils, eosinophils and dendritic cells. ADCC is a rapid domain or in the intracellular domain of the associated
effector mechanism whose efficacy is dependent on a transducing unit termed g chain), a cytotoxic pathway is
number of parameters (density and stability of the anti- initiated that results in the release of mediators such as
gen on the surface of the target cell; antibody affinity and perforin, granzymes, tumour necrosis factor (TNFa) and
reactive oxygen intermediates (ROI) – which induce target
FcR-binding affinity). ADCC involving human IgG1, the
cell death. Conversely, ligation of inhibitory FcR (char-
most used IgG subclass for therapeutic antibodies, is
acterised by the presence of an immunoreceptor tyrosine-
highly dependent on the glycosylation profile of its Fc based inhibitory motif (ITIM) in their IC domain) prevents
portion and on the polymorphism of Fcc receptors. effector cell activation, resulting in survival of the target
cell.

Introduction
Fc Receptors are Trigger Molecules
Antibody-dependent cell-mediated cytotoxicity (ADCC) for ADCC
was initially described by Moller in 1967 as the ability of
natural killer (NK) cells – at the time identified only as
As noted earlier, FcR on the surface of cytotoxic effector
lymphocytes – to destroy antibody-coated target cells. A
cells are required for ADCC (Fanger et al., 1989). Separate
nonphagocytic mechanism, whereby most leucocytes can
genes that are members of the immunoglobulin (Ig)
kill target cells in the absence of complement and without
supergene family encode different FcR: FcgR specifically
major histocompatibility complex (MHC) restriction (a
bind IgG, FcaR bind IgA, FceR bind IgE and Fcm/aR bind
mechanism by which specific cytotoxic T cells (CTLs) kill
both IgM and IgA (van Egmond et al., 2001a; Dombrowicz
target cells expressing peptides loaded onto surface MHC
et al., 2000; Kinet and Launay, 2000; Ravetch and Bolland,
Class I molecules) thus became apparent. The specificity of
2001; van der Poel et al., 2011). In humans, it is clear that
members of the following FcR classes are all capable, when
eLS subject area: Immunology crosslinked, of activating ADCC: FcgRI (CD64), FcgRIIa
and FcgRIIc (CD32), FcgRIIIa (CD16) (Figure 1), FcaR
How to cite: (CD89) and FceRI. In mouse, ADCC can be achieved
Teillaud, Jean-Luc (July 2012) Antibody-dependent Cellular
through the crosslinking of FcgRI, FcgRIII and FcgRIV as
Cytotoxicity (ADCC). In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0000498.pub2
there is no activating FcgRIIa (Nimmerjahn and Ravetch,
2008). In addition, it has also been shown that engagement

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Antibody-dependent Cellular Cytotoxicity (ADCC)

FcRI
FcRIIIA FcRIIA/C
(CD64)
(CD16) (CD32)

  ( or )

High affinity Intermediate affinity Low affinity


(PMNC, monocytes/MΦ) (NK, MΦ) (Monocytes, MΦ, NK)

Figure 1 Schematic view of human-activating FcgR. In most cases, human-activating Fcg receptors comprise an IgG binding a chain associated with a
transducing subunit, a g chain (gg) homodimer. In NK cells, the presence of a g/z heterodimer or of a z/z homodimer has also been reported (the z chain is
also part of the T cell receptor (TcR) complex). The associated g or z chain contains an ITAM (immuno-receptor tyrosine-based activating motif) (black
square) that is phosphorylated upon crosslinking of FcgR. Human FcgRIIa is the only activating receptor where the IgG-binding a chain intracellular domain
contains an ITAM, although its association with a transducing g chain homodimer has been debated. Myeloid cells can express both activating and inhibitory
FcgRIIb (not shown in the diagram) and it is considered that cellular activation will result from the fine tuning of the balance between activating and
inhibitory signals. NK cells express activating FcgRIIIa, although the expression of activating FcgRIIc and of inhibitory FcgRIIb by small NK cell subsets has also
been reported. FcgRIIIa is also expressed by some T cells. FcgRIIIb, a GPI-linked surface receptor expressed by neutrophils is not presented. In mouse, there is
no FcgRIIa and inhibitory FcgRIIb is referred only as FcgRII. In contrast, there is another activating FcgR, termed FcgRIV, also associated with a g chain
homodimer.

of mouse inhibitory FcgRII leads to inhibition of ADCC et al., 2008), but whether these receptors impact NK cell-
activation (Clynes et al., 2000). The balance between acti- mediated ADCC mediated through FcgRIIIa in some
vating and inhibitory FcgR thus appears to be a crucial circumstances remains to be elucidated.
determinant of the magnitude of ADCC that is induced
when the effector cell engages the antibody-coated target Monocytes, macrophages and dendritic cells
and expresses both types of Fc receptors (Nimmerjahn and
Ravetch, 2008; Abes et al., 2009). See also: Antibodies; Monocytes and macrophages express all three classes of
Antibody Classes; Antibody Function; Fc Receptors; IgG receptors, FcgRI (CD64), FcgRII (CD32) and
Hypersensitivity: Antibody-mediated Cytotoxic (Type II) FcgRIII (CD16) (see Figure 1), as well as the receptor for
IgA (CD89) (Ravetch and Bolland, 2001; van Egmond
et al., 2001a; Nimmerjahn and Ravetch, 2008). Each has
been shown to be capable of triggering phagocytosis and
Cellular Effectors of ADCC ADCC by monocytes and macrophages. Although only
low levels of FcgRIIIa are expressed on freshly isolated
Natural killer cells monocytes, this receptor can be markedly increased when
monocytes mature into macrophages or are cultured with
NK cells are perhaps the most reliable effectors of ADCC activating cytokines such as interferon g (IFNg). Cytokine
when tested in cell culture cytotoxicity assays (Perussia, activation has also been shown to induce expression of
2000). When freshly isolated from circulating blood, a large FceRI. It has been noted that activated macrophages have
subset of human NK cells (defined as CD56dim CD16+) high FcgRIIIa/IIb ratios, favouring cell activation,
express relatively high levels of the type IIIa IgG receptor whereas quiescent effectors have low IIIa/IIb ratios, pro-
(FcgRIIIa or CD16a) and very efficiently mediate ADCC viding a high threshold for cell activation (Ravetch and
of tumour cells that are coated with antitumour IgG (Figure Lanier, 2000; Nimmerjahn and Ravetch, 2008). Human
2). NK cells appear not to express other classes of Fc blood dendritic cells also express IgG FcR and are potent
receptors and, therefore, are not activated for ADCC by effectors in antibody-dependent cellular cytotoxicity
IgA, IgE or IgM. FcgRIIIa is present on both NK cells and (Schmitz et al., 2002). In mouse, a critical role of FcgRIV in
macrophages as a transmembrane receptor that is associ- ADCC mediated by monocytes, macrophages and neu-
ated with the FcR g chain, an activating molecule involved trophils has been suggested using FcgRIV-deficient mice
in signal transduction. This association with the g chain (Nimmerjahn et al., 2010).
was found to be essential both for surface expression of
FcgRIIIa and for signal transduction following engage- Neutrophils and eosinophils
ment of this receptor by IgG. In contrast, FcgRIIIb
(CD16b) found on human neutrophils is expressed as a Freshly isolated neutrophils do not lyse tumour targets
phosphatidyl inositol glycan-linked receptor that does not through FcgR, but can be activated by granulocyte–
associate with the g chain and does not activate tumour cell macrophage colony-stimulating factor (GM-CSF) to
killing. Only FcgRIIIa, and not FcgRIIIb, is found in mice. mediate killing through FcgRIIa, and by IFNg to mediate
The expression of activating FcgRIIc and of inhibitory killing through FcgRI and FcgRIIa. The type of FcgRIII
FcgRIIb on small subsets of circulating NK cells has been expressed by human neutrophils (FcgRIIIb, a GPI-linked
reported (Metes et al., 1994; Sulica et al., 2001; Dutertre surface receptor) does not mediate cytotoxicity of tumour

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Antibody-dependent Cellular Cytotoxicity (ADCC)

targets, even following cell activation by cytokines. On the


contrary, FcgRIIIa on murine polymorphonuclear neu- Tumor antigen
trophil (PMN) does induce ADCC of tumour cells. Cyto- FcR
lysis of red blood cells occurs via FcgRIIa, FcgRIIIa and
FcgRIIIb even when resting human neutrophils are used as
Tumor cell
effectors. These observations suggest that erythroid and
tumour targets are killed through different pathways, and
that triggering of FcgRIa or FcgRIIa on neutrophils acti- FcR+ cell
vates lytic mechanisms distinct from those initiated via
FcgRIIIb (Fanger et al., 1989). Of particular interest,
Anti-tumor mAb
neutrophils can efficiently kill human IgA-coated tumour
cells and ADCC is highest when both IgA and IgG recep-
tors are coordinately triggered (van Egmond et al., 2001b). Figure 2 Schematic view of ADCC. The binding of an IgG antitumour
Furthermore, freshly isolated neutrophils carry out FcaR- mAb to the target cell (here a tumour cell) allows the recruitment and
dependent lysis without cytokine preactivation, although crosslinking of activating FcgR expressed by effector cells (NK cells,
to a low level. Treatment of donors with granulocyte col- neutrophils, etc.). In humans, activating receptors include FcgRI (CD64),
FcgRIIa (CD32) and FcgRIIIa (CD16). In mouse, they include FcgRI, FcgRIII
ony-stimulating factor (G-CSF) leads to an upregulation
and FcgRIV. Effector cells are then activated and release molecules that will
of FcgRI and enhanced ADCC by neutrophils (Dechant lead to the death of tumour cells. The diagram represents a NK cell
et al., 2007). containing granules that polarised towards the contact zone with tumour
Although freshly isolated eosinophils express FcgRII as cell once FcgRIIIa (CD16) has been engaged and crosslinked. The granule
well as low levels of FcgRIII and FceRI, they are not potent content (perforin and granzyme B) is then released in the close vicinity of
the tumour cell (NK cell ‘synapse’), initiating an apoptotic process that will
ADCC effectors unless activated with GM-CSF, inter- lead to cell death.
leukin 3 (IL-3) or IL-5. After cytokine activation, killing of
tumour or erythrocyte targets is mediated through FcgRII
but not FcgRIII. Thus, like neutrophils, eosinophils identified within the cytoplasmic domain of the so-called
require cytokine activation to perform ADCC through alpha or immunoglobulin-binding chains of some FcR
FcgRII. Also, like neutrophils, freshly isolated eosinophils (e.g. FcgRIIa), and also within associated signalling mol-
are able to mediate ADCC via FcaRI. Eosinophils have ecules (e.g. g chain in the case of FcgRI, FcgRIIIa, FcaRI
also been shown to mediate ADCC of parasites via FceR and FceRI, and mouse FcgRIV). Granule release is
following activation by cytokines (Dombrowicz et al., dependent on activation of the mitogen-activated protein
2000) and of tumour cells via FcgRI (Karagiannis et al., kinase (MAPK) family member ERK (extracellular signal-
2007). related kinase) and includes intermediate interactions
involving the p56lck and many other protein tyrosine
kinases (reviewed by Perussia, 2000).
Mechanisms of Cytotoxicity Many studies have focused on dissecting the mechanisms
of target cell destruction mediated by cytolytic CTL and
It is now well established that antibodies act as a bridge NK effector cells. Although the manner in which T cells and
between FcR on the effector cell and the target antigen on NK cells recognise their targets is different, these cells share
the cell that is to be killed. Crosslinking of receptors is similar cytotoxic mechanisms. Upon recognition of target,
required to activate the cytotoxic event (Figure 2). Even for the contents of specialised intracellular granules (also
high-affinity receptors, binding of monomeric Ig is insuf- termed secretory lysosomes) within the effector cell are
ficient to transmit an activation signal. The nature of the released by a calcium-dependent polarised exocytotic
biological response and the subsequent cytotoxicity initi- process at the lytic synapse (de Saint Basile et al., 2010). The
ated by FcR crosslinking depends on the integration of a NK cell synapse involves the reorganisation of the actin
variety of signals that are dependent on the class and sub- cytoskeleton and the clustering of some membrane recep-
class of both the antibody and the FcR involved, on acti- tors in the NK cell at the contact with the target cell
vation of other signalling molecules, on the effector cell (Orange, 2007). Perforin, or cytolysin, is one component
type, and on the nature of the target cell. Cell surface that is released from granules. Perforin inserts and poly-
molecules other than FcR also may play a role by pro- merises within the target cell membrane, in a manner that is
moting adhesion between effector and target cells and/or analogous to the membrane insertion of the terminal
by providing synergistic signals. components of the complement cascade, resulting in the
Crosslinking of activating FcR initiates a signalling formation of a pore in the target cell. Calcium is required
cascade that culminates in release of cytoplasmic granules for the insertion and assembly of perforin in the target cell
and the synthesis of surface activation molecules including membrane. A critical role for perforin in host immune
CD69 and CD25 (the g chain of the high affinity IL-2 defence has been confirmed in perforin-deficient mice.
receptor). It often begins with the stimulation of ITAM Other components of granules released by exocytosis have
sequences (Billadeau and Leibson, 2002; Ravetch and also been implicated in the mechanism of CTL and NK
Lanier, 2000). As discussed earlier, ITAMs have been cell-mediated cytotoxicity. One such granule component,

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Antibody-dependent Cellular Cytotoxicity (ADCC)

granzyme B, may be involved in deoxyribonucleic acid requirement for active participation of the effector cell such
(DNA) fragmentation observed in target cells after as release of toxic mediators by the effector cell. This has
engaging a cytotoxic effector cell. However, studies using been shown with anti-CD20 antibodies whose binding to
granzyme B-deficient mice suggest a less important role for CD20 expressed by lymphoma cells triggers a significant
granzyme B in cytotoxicity. Molecular studies of patients apoptosis only when a FcgR-mediated crosslinking has
with inherited defects that impair cytotoxic functions have been achieved.
also helped to decipher the intimate mechanisms of cyto- In conclusion, multiple pathways may be involved in
toxicity by NK cells. Notably, it has been shown that the how an effector cell mediates ADCC of an antibody-
cytotoxic function requires the cooperation of the lysoso- opsonised target cell. These include perforin, cytolytic
mal cytotoxic granule and the endosomal exocytic vesicle. enzymes, reactive oxygen intermediates and apoptotic
A rapid polarisation of these two types of granules is signalling both with dependent and independent of Fas/
observed, followed by a coalescence near the cell–cell FasL interactions. Several mechanisms may combine to
contact area (Ménager et al., 2007). In vivo imaging mediate cytotoxicity depending on a variety of factors. The
experiments have shown that tumour cells form stable relative importance of each in vivo and ex vivo will continue
conjugates with macrophages and neutrophils expressing to be dissected using knockout mice and/or effector cells
FcgRs in tumour-bearing mice treated with a tumour- from individuals deficient in specific effector mechanisms.
specific antibody (Hubert et al., 2011). The contact zone Intra-vital imaging and in vitro imaging analyses should
accumulated actin, FcgR and phosphotyrosines. These in make it possible to better understand the in vivo dynamics
vivo ADCC synapses appear to be organised in multifocal of ADCC and the formation of the ADCC synapse.
supra-molecular activation clusters. Another mechanism
of target cell destruction is the engagement of Fas by Fas
ligand (FasL), molecules expressed, respectively, on the
surface of some target and effector cells. This interaction Inhibition of Cytotoxicity
initiates a cascade of signals in the target cell resulting in
apoptosis of the target. Crosslinking of FcgRIIIa on NK Fine tuning between activating and inhibitory pathways is
cells induces the expression of FasL, enabling them to kill now also understood to be a critical determinant of ADCC
Fas+ targets. Therefore, FasL/Fas interaction may be an activity (Billadeau and Leibson, 2002; Ravetch and Lanier,
important mechanism of ADCC mediated by NK cells. 2000; Nimmerjahn and Ravetch, 2008). FcgRIa (CD64),
Myeloid cells are able to destroy antibody-opsonised FcgRIIa (CD32) and FcgRIIIa (CD16a); FcaR (CD89)
targets by phagocytosis as well as by extracellular lysis. and FceRI are all capable of mediating ADCC when
Targets ingested phagocytically are destroyed in intracel- engaged by their respective ligands and crosslinked. Con-
lular phagolysosomes of the effector cell. The mech- versely, an inhibitory signal is generated upon crosslinking
anism(s) by which myeloid cells mediate extracellular lysis of FcgRIIb which contains cytoplasmic ITIM sequences,
of antibody-opsonised target cells has been controversial. aborting cellular activation through ITAM-containing
It is clearly different from ADCC mediated by NK cells. In receptors. The presence or absence of signalling through
one in vitro system, the mechanism of ADCC mediated by other immune inhibitory receptors on ADCC effector cells
myeloid cells has been shown to be distinct from that also influences cytotoxic activity. These receptors, with
mediated by NK cells based on divalent cation require- acronyms such as killer inhibitory receptor (KIR) (or
ments (Graziano et al., 1989). ADCC mediated by NK cells CD158), CD94/NKG2 (NKG2, an activating receptor
via FcgRIII was Ca2+ dependent and Mg2+ independent. for Natural Killer cells is also known as CD159a) and
In contrast, ADCC mediated by monocytes or by IFNg- immunoglobulin-like transcript (ILT) (also called leuco-
activated PMN via FcgRIa or FcgRIIa, or by peritoneal cyte inhibitory receptor (LIR or CD85)) associate with
macrophages via FcgRIa, FcgRIIa or FcgRIIIa was Mg2+ SHP-1 (Src homology region 2 domain-containing phos-
dependent and Ca2+ independent. Thus, even though phatase-1) and SHP-2 (Src homology region 2 domain-
macrophages and NK cells both mediate ADCC via containing phosphatase-2) phosphatases to inhibit cell
FcgRIIIa, the mechanism by which these two types of activation.
effector cells mediate their killing is distinct. Monocytes, The effect of FcgRIIb on ADCC and tumour growth
macrophages and neutrophils release ROI when FcR in vivo was demonstrated in FcgRIIb-deficient mice. Using
are crosslinked, and ROI have been implicated as the models of antibody-mediated tumour treatment, Clynes
mediators of target cell death. However, other mechanisms et al. (2000) demonstrated that FcgRIIb-deficient mice were
must also exist since neutrophils isolated from patients with able to inhibit tumour growth and protect from tumour
chronic granulomatous disease (CGD), whose cells lack metastasis as compared with wild-type mice. This finding
the ability to form ROI, were able to mediate ADCC as confirmed that FcgRIIb acted as an inhibitory receptor.
well as neutrophils isolated from normal donors (Roberts One interesting development of this observation has been
et al., 1993). Finally, it has been shown that when antibody the generation of antitumour IgG antibodies that weakly
binds to an apoptotic trigger molecule on the target bind the inhibitory FcgRIIb, whereas strongly engaging
cell, FcR crosslinking of the target-bound immunoglobulin activating receptors (Shields et al., 2001; Stavenhagen
can induce apoptotic cell death, apparently without a et al., 2007).

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Antibody-dependent Cellular Cytotoxicity (ADCC)

Regulation of ADCC Role of ADCC in Host Immunity


The ability of an effector cell to mediate ADCC depends on Early studies showed that tumour-specific antibodies that
a variety of parameters including the type of effector cell, were effective in promoting ADCC in vitro were also effi-
the class of FcR(s) engaged, the number of FcR per cell and cacious in curing tumours in vivo using mouse models
the state of activation of the effector cell. Treatment of (Herlyn and Koprowski, 1982). This correlative evidence
effector cell populations with cytokines or other physio- was confirmed recently in studies using mice deficient in
logical mediators may increase or decrease the expression FcRg. FcRg refers to the g chain-signalling molecule that
level of a particular FcR on an effector cell, thereby was initially described as a subunit of FceRI, but later
enhancing or depressing ADCC through that receptor. shown to be required for optimal expression of – and signal
Cytokine treatment may also change the activation state of transduction by – FcRgRIa and FcRgRIIIa (and FcgRIV
an effector cell leading to enhanced or depressed ADCC in mice). NK cells and macrophages from FcRg–/– mice are
without altering the number of FcR on the effector cell. The deficient in expression of these activating FcRgR and
expression of other molecules on the effector cell such as ineffective in mediating ADCC in vitro. The physiological
inhibitory receptors or adhesion molecules also impacts the importance of this deficiency has also been demonstrated in
ability of an effector cell to mediate ADCC. It seems likely vivo. Functional FcR were required for both passive and
that the specific tissue microenvironment, which dictates active immunity to tumours. Whereas, human IgG1 and
the overall molecular interactions of the FcR-bearing cell, murine IgG2a antitumour antibodies dramatically
plays a crucial role in the ultimate level of function that is inhibited tumour growth in intact mice, they were without
triggered by engagement of FcR. effect in FcRg –/– mice (Clynes et al., 2000). Similarly, when
IFNg is a potent modulator of ADCC. Treatment of the FcR of an antitumour antibody was mutagenised to
monocytes, macrophages or neutrophils with IFNg eliminate its binding to FcRgRIII, it lost its capacity to
increases the expression level of FcgRIa on these cells more inhibit tumour growth in vivo. Of note, when mice no
than 10-fold, owing to the presence of interferon-stimu- longer expressing inhibitory FcgRIIb were used, a strong
lated response elements (ISREs) in the FCGR1 gene pro- improvement in the ability of therapeutic antibodies to
moter. ADCC mediated via FcgRIa is similarly increased, prevent tumour growth was observed, indicating that the
especially when limited amount of antibody is available on overall balance between activating and inhibitory FcgR is
the target. Interestingly, even though IFNg treatment does indeed crucial for the antitumour activity of antibodies
not increase the expression level of FcgRIIa on neutrophils, (Clynes et al., 2000).
it does enable ADCC FcgRIIa, perhaps by altering the Evidence implicating the role of ADCC in human host
cytotoxic potential of the neutrophil or by changing the immunity had been mostly circumstantial until the early
FcgRIIa/FcgRIIb ratio. Furthermore, IFNg induces 2000s. It was mostly based on several reports correlating
higher expression of the Fc receptor g chain that is essential the ability of human effector cells to mediate ADCC, or the
for ADCC triggered through FcgRIa, and may also par- presence of ADCC-mediating antibody titres, with the lack
ticipate in signal transduction following engagement of of disease progression. For example, in one study, ADCC
FcgRIIa and FcgRIIIa. activity of mononuclear cells isolated from immuno-com-
Enhancement of ADCC by cytokines other than IFNg promised human immunodeficiency virus (HIV) patients
has also been demonstrated. Both interleukin 2 (IL-2) and correlated with longer survival in these patients (Forthal
IL-15 that activate NK cells and induce an upregulation of et al., 1999). In a separate study, the levels of ADCC
FcgRIIIa expression stimulate strongly ADCC exerted by activity via anti-gp120 antibodies in serum of HIV-1
anti-CD20 (rituximab) and anti-epidermal growth factor positive individuals correlated with successful host defence
(EGFR; cetuximab) antibodies against tumour cells as defined by rate of progression to acquired immune
(Golay et al., 2003; Roberti et al., 2011). GM-CSF and deficiency syndrome (AIDS). Furthermore, effector cells
TNFa enhance ADCC by monocytes cultured in vitro isolated from humans that were capable of mediating
through FcgRI, FcgRII and FcaRI. ADCC mediated by ADCC in conjunction with antibody to herpes simplex
PMN via FcgRII is enhanced by in vitro culture in the virus (HSV) were able to protect neonatal mice from lethal
presence of G-CSF. Treatment of patients in vivo with G- infection with HSV. Some bacterial pathogens have
CSF or IFNg leads to the upregulation of FcgRI and developed mechanisms to disrupt Ig–FcR interactions in
FcaRI on neutrophils and enhanced ex vivo ADCC via this order to circumvent ADCC or phagocytosis. These
receptor (Valerius et al., 1993; Dechant et al., 2007). This mechanisms provide the pathogens an advantage by
observation has led to the development of bi-specific anti- interfering with host clearance mechanisms implicating the
bodies (engineered antibodies directed against a tumour- importance of ADCC and phagocytosis in host immunity.
associated antigen expressed on tumour cells and against The role of ADCC in human host immunity has been
FcgRI expressed by killer cells) for treating cancer patients strongly highlighted by a number of reports on the impact
in combination with G-CSF (Michon et al., 1995; Repp of FcgR polymorphism on the clinical outcome of cancer
et al., 1995) and, recently, to the development of recom- patients. FcgRIIIa gene exhibits a polymorphism because
binant antibodies directed against EGFR (Dechant et al., of a single nucleotide change leading to the presence at
2007). position 158 of either a valine or a phenylalanine. The

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Antibody-dependent Cellular Cytotoxicity (ADCC)

presence of phenylalanine makes FcgRIIIa a weaker include target cell apoptosis as well as effector cell release of
binder to human IgG1 as compared with FcgRIIIa har- toxic molecules such as perforin, granzyme B, TNFa,
bouring a valine. It has been demonstrated in vitro that NK reactive oxygen and reactive nitrogen.
cells derived from Val/Val homozygous donors exhibit a
stronger ADCC against IgG1-coated tumour cells as
compared with Phe/Phe donors. Interestingly, an associ-
ation between the FCGR3A genotype and clinical and References
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