Blockade of clearance of immune complexes by an anti-F(cγ) receptor monoclonal antibody

Clarkson, S B; Kimberly, Robert P.; Valinsky, JE; Witmer,; Bussel, J B; Rl, Nachman; Unkeless, JC

doi:10.1084/jem.164.2.474

Cited by 171 publications

(87 citation statements)

References 32 publications

(23 reference statements)

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“…These data suggest that the high-affinity FcR may not efficiently promote phagocytosis. Consistent with this hypothesis are the observations that >70% of the uptake of EIgG is inhibited when the low-affinity FcR is removed from MO (27), and clearance of IgGcoated erythrocytes is decreased 98% by antibodies against a low-affinity receptor (28). These observations suggest that phagocytosis of IgG-coated particles by MO may be promoted primarily by a low-affinity FcR, not by the high-affinity FcR induced by IFN-% Summary Cultivation of human monocytes with recombinant IFN-7 causes a 5-10-fold depression in their binding of EC3b or EC3bi.…”

Section: Ifn-'r Does Not Alter the Mobility Of Cr3supporting

confidence: 69%

Interferon-gamma depresses binding of ligand by C3b and C3bi receptors on cultured human monocytes, an effect reversed by fibronectin.

Wright¹,

Detmers²,

Jong³

et al. 1986

The Journal of Experimental Medicine

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Receptors for C3 bind ligand and generate intracellular signals that lead to the engulfment of C3-coated particles. Recent experiments suggest that both the binding and the subsequent signal transduction activities of C3 receptors can be regulated. Cultured human monocytes (MO) 1 express receptors for C3b (CR1) and C3bi (CR3) that bind ligand-coated particles but do not signal the cell to initiate phagocytosis. After stimulation of the MO with PMA (1), or after interaction of the MO with surfaces coated with fibronectin (Fn, reference 2), CR1 and CR3 readily generate signals leading to phagocytosis. Thus PMA and Fn regulate the signaling capacity of CR1 and CR3 in these cells. In polymorphonuclear leukocytes, both the binding and the signaling activities are coordinately regulated. Brief (15 min) stimulation with PMA increases binding and signaling activities of CR 1 and CR3, but prolonged (60 min) incubation with PMA eliminates both binding and signaling (3). Since the PMA-mediated decline in the binding capacity of CR1 and CR3 is not accompanied by a loss of cell surface receptors, it appears that PMA regulates the binding and signaling activities of existing cell surface receptors.In this report, we show that treatment of human monocytes and MO with recombinant IFN-~, causes CR1 and CR3 to lose the ability to bind ligand. IFN-"),-treated cells express normal levels of cell surface CRI and CR3 as measured with anti-receptor antibodies, and the inhibition of ligand binding by CR 1 and CR3 is reversed in minutes by interaction of the phagocytes with Fn-coated surfaces. Therefore, cultivation with IFN-~, causes a reversible change in the nature of these receptors, which prevents them from interacting with ligand.

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Section: Ifn-'r Does Not Alter the Mobility Of Cr3supporting

confidence: 69%

Interferon-gamma depresses binding of ligand by C3b and C3bi receptors on cultured human monocytes, an effect reversed by fibronectin.

Wright¹,

Detmers²,

Jong³

et al. 1986

The Journal of Experimental Medicine

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“…The receptor that plays a predominant role in clearance of large immune complexes is Fc yRIII or CD16. Blockade of FcyRIII in chimpanzees with the anti-FcyRIII mAb 3G8 or its Fab fragment resulted in a 20-fold increase in clearance time for IgG-sensitized chimpanzee erythrocytes (28). Antibody against FcyRIII allotypes NA1 and NA2 has been associated with juvenile neutropenia (29,30), and anti-FcyRIII antibody has also been identified in sera of patients with SLE (31).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune mice make anti-Fc gamma receptor antibodies.

Boros

Chen

Bona

et al. 1990

The Journal of Experimental Medicine

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Hallmarks of autoimmune diseases such as SLE are hypergammaglobulinemia, the production of autoantibodies, and elevated levels of circulating immune complexes . Several mouse strains are used as models of SLE (see reference 1 for review), including NZB, NZB/NZW Ft , MRL/lpr, and BXSB . In human and murine SLE, there is frequently a .pronounced inhibition of macrophage binding and phagocytosis of IgG-sensitized erythrocytes and immune complexes (2-4) . One possible reason for this inhibition is the downmodulation of the macrophage Fcy R after binding of immune complexes . An alternate explanation for the inhibition of Fc yR function might be the binding of anti-Fcy R autoantibody to the macrophage FcyR .In this study, we have used a recombinant truncated FcyR (tFcyR) t to screen murine sera and mAbs for naturally occurring anti-Fcy R antibody. The tFcyR is derived from murine FcyRIIf, and consists of the two external Ig-like domains of muFcy RIIa, but lacks the transmembrane and cytoplasmic domains of the receptor (5) . We report here the presence and characterization of anti-Fcy R antibodies in sera ofsome mice genetically prone to autoimmune diseases and anti-Fc yR hybridomas derived from NZB and motheaten (me") mice.Volume 171 May 1990 1581-1595 AUTOIMMUNE MICE MAKE ANTI-Fcy RECEPTOR ANTIBODIES Materials and Methods mAbs and Sera. The mAbs that we screened for anti-FcyR activity were derived from fusions with spleen cells from old NZB mice or young NZB mice after stimulation with LPS (6) . Other hybridomas screened were from unstimulated viable me' mice (7) . The IgM mAbs were all purified by affinity chromatography on an anti-tc IgG-Sepharose column and were eluted from the column with 0 .1 M glycine HCI, pH 2 .3 . Samples of sera from NZB, NZB/NZW F,, MRL/lpr, and BXSB mice were kindly given to us by Dr. Argyris Theofilopoulos (Scripps Clinic, La Jolla, CA) . Sera from me', tightskin mouse (TSK), C57B1 .6pa/pa, and C58/J were obtained from animals purchased from The Jackson Laboratory (Bar Harbor, ME). Anti-DNP hybridomas DHK109 .3 (IgGl) and DHK10 .12 (IgG2b)

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“…Under these conditions, it is likely that the capacity of effector cells of the mononuclear phagocytic system (MPS), expressing Fc␥RII and Fc␥RIII (15, 74 -76), is sufficient to take up and destroy the RTX-opsonized cells. However, infusion of the standard dose of RTX in CLL patients with high circulating B cell burdens is likely to lead to saturation of the cellular clearance mechanisms mediated by the MPS (43). That is, the large number of RTX-opsonized cells may overwhelm the most immediate clearance and killing capacity of the MPS, and under these conditions a secondary reaction occurs: the shaving of RTX-CD20 complexes from the the highly opsonized B cells (34,77,78).…”

Section: Relevance Of Shaving To Rtx Therapy For Cllmentioning

confidence: 99%

The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

Beum

Kennedy

Williams

et al. 2006

The Journal of Immunology

204

226

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Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcγR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20+ cells with acceptor THP-1 monocytes. After 45 min at 37°C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab′)2 of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcγR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.

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Blockade of clearance of immune complexes by an anti-F(cγ) receptor monoclonal antibody

Cited by 171 publications

References 32 publications

Interferon-gamma depresses binding of ligand by C3b and C3bi receptors on cultured human monocytes, an effect reversed by fibronectin.

Interferon-gamma depresses binding of ligand by C3b and C3bi receptors on cultured human monocytes, an effect reversed by fibronectin.

Autoimmune mice make anti-Fc gamma receptor antibodies.

The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

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