Immune Complexes Bound to the Primate Erythrocyte Complement Receptor (CR1) via Anti-CR1 Mabs Are Cleared Simultaneously with Loss of CR1 in a Concerted Reaction in a Rhesus Monkey Model

Taylor, Ronald P.; Ferguson, Polly J.; Martin, Edward N.; Cooke, James; Greene, Kirsten L.; Grinspun, Kenneth; Guttman, Marc; Kuhn, Susan

doi:10.1006/clin.1996.4286

Cited by 39 publications

(37 citation statements)

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“…Further examination of the transfer of the AHP ICs suggests that CR1 is lost from the erythrocytes during transfer ( Figure 6), perhaps through the action of a metalloprotease. These results, taken in the context of previous in vivo studies (15,16,31,32,34), provide additional evidence that AHP-induced in vivo clearance of autoantibodies from the circulation should be mediated by the body's natural mechanism for IC clearance. We developed a model, illustrated in Figure 7, for the transfer of CR1-bound IC from erythrocytes to acceptor phagocytes.…”

Section: Discussionsupporting

confidence: 70%

“…The AHP construct allows for the binding of anti-dsDNA antibodies to erythrocyte CR1 in the complete absence of complement (31). Our findings in monkey models, with prototype HP and AHP ICs, suggest that the mAb specific for CR1 serves as a surrogate for C3b and that the mechanism of clearance of ICs bound to primate erythrocytes via anti-CR1 mAb follows the same pathway as the "natural" transfer reaction, in which the ICs are bound to erythrocyte CR1 after opsonization with C3b (4,12,(31)(32)(33)(34).…”

mentioning

confidence: 76%

“…Our studies in nonhuman primates implicate Fc receptors by demonstrating that erythrocyte CR1-bound ICs containing whole IgG mAb are cleared within minutes, while those containing F(abЈ) 2 fragments (lacking IgG Fc) are cleared more slowly (4). Moreover, clearance of the whole IgG IC occurs with a corresponding loss of erythrocyte CR1 (4,34,51). In humans, IC clearance studies by Davies et al (15,16) and reports of reduced erythrocyte CR1 levels in patients with diseases characterized by chronic IC processing (52-54) also suggest that CR1 is lost during processing of CR1-bound ICs (53).…”

Section: Discussionmentioning

confidence: 99%

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Clearance of anti-double-stranded DNA antibodies: The natural immune complex clearance mechanism

Craig

Bankovich

McElhenny

et al. 2000

Arthritis & Rheumatism

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Objective. To develop an in vitro model for investigating the mechanism by which autoantibodies in immune complexes (ICs) that are bound to primate erythrocytes via antigen-based heteropolymers (AHPs) are cleared from the circulation and localized to the liver.Methods. IgG anti-double-stranded DNA (antidsDNA) antibodies in ICs with dsDNA were bound to human erythrocytes via complement receptor 1 (CR1) either by opsonization with normal human serum as a complement source or through the use of an AHP, which consists of an anti-CR1 monoclonal antibody (mAb) that is chemically crosslinked with dsDNA. We performed parallel investigations of the mechanism of transfer of both types of erythrocyte-bound ICs to a monocytic cell line (U937). Erythrocytes with CR1-bound ICs were incubated with U937 cells under a variety of conditions, and subsequently, the levels of IgG anti-dsDNA, CR1, AHP, or C3b on both erythrocytes and U937 cells were measured by flow cytometry with appropriate fluorescently labeled probes.Results. In the presence of U937 cells, both the AHP-anti-dsDNA and C3b-opsonized ICs were rapidly removed from the erythrocytes; at 37°C, more than half of the complexes were removed in 2 minutes. Monomeric mouse IgG2a mAb blocked the transfer of both types of complexes by 75%, suggesting that Fc␥ receptor type I (Fc␥RI) is the main phagocyte receptor responsible for the removal of ICs from erythrocytes. Levels of CR1 on the erythrocyte surface were reduced during transfer of the AHP-anti-dsDNA ICs, suggesting that transfer involves a concomitant removal of CR1, presumably by proteolysis.Conclusion. Transfer of AHP-anti-dsDNA ICs from erythrocyte CR1 to model phagocytes occurs by a mechanism that is similar to the natural mechanism of IC clearance, involving recognition by Fc␥RI and removal of erythrocyte CR1 as key steps.

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Section: Discussionsupporting

confidence: 70%

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confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Clearance of anti-double-stranded DNA antibodies: The natural immune complex clearance mechanism

Craig

Bankovich

McElhenny

et al. 2000

Arthritis & Rheumatism

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“…Furthermore, many of these proteases are known to be able to cleave certain membrane-associated proteins, which like CR1 are composed of the short consensus repeat structural motif (44 -47). Finally, studies in monkey models and in humans of the processing of substrates bound to E CR1 in the circulation have suggested that loss and/or proteolysis of CR1 is a key step in the clearance reaction (5,6,33,34). The present series of in vitro investigations provide strong support for this model.…”

Section: Discussionsupporting

confidence: 57%

“…Our previous work in monkey model systems has indicated that these E-bound IC, generated in the circulation by infusion of X174 followed by specific HP, are indeed removed from the E and cleared to the liver (15). Studies with other systems in monkey models suggested that loss of CR1 from the E is a key required step in this reaction (33,34). We chose to focus primarily on a mouse macrophage cell line to eliminate the potential confounding effect of human CR1 located on the acceptor macrophage.…”

Section: Discussionmentioning

confidence: 99%

Transfer of Immune Complexes from Erythrocyte CR1 to Mouse Macrophages

Reinagel

Taylor

2000

The Journal of Immunology

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We are developing a potential therapeutic approach for removing pathogens from the circulation of primates in which the pathogen is bound to the complement receptor (CR1) on E using a bispecific mAb complex, a heteropolymer (HP). We have used mAb this approach to demonstrate that cleared prototype pathogens are localized to, phagocytosed in, and destroyed in the liver. Extension of this work to a clinical setting will require a detailed understanding of the mechanism by which the E-bound immune complex substrates are transferred to fixed tissue macrophages in the liver, the transfer reaction. Therefore, we examined an in vitro system to study this process using bacteriophage φX174 as a model pathogen. E containing φX174 (bound via an anti-CR1/anti-φX174 HP) were incubated with P388D1 murine macrophages, and the two cell types were separated by centrifugation through Ficoll. Both E and macrophages were then probed and analyzed by RIA or flow cytometry. The results indicate that all three components of the E-bound IC (φX174, HP, and CR1) were removed from the E and internalized by the macrophages. We found that transfer requires the Fc portion of IgG, because little transfer of φX174 occurs when it is bound to E CR1 using a HP containing only Fab fragments. These findings, taken in the context of other studies, suggest a general mechanism for the transfer reaction in which Fc receptors facilitate close juxtaposition of the macrophage to the E-bound IC which then allows a macrophage-associated protease to cleave CR1. The released IC are then internalized and processed by the macrophages.

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A prototype pathogen boundex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody complexes is cleared to the liver in a mouse model

et al. 1999

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A prototype pathogen bound ex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody complexes is cleared to the liver in a mouse model Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to the liver. IC can be bound to E CR1 either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain an mAb specific for CR1 and a mAb specific for a prototype pathogen. The long-term goal of our work is to apply the HP to the treatment of human diseases associated with blood-borne pathogens. Therefore we have investigated the feasibility of a non-primate model by studying clearance in mice of bacteriophage ¤ X174 bound via HP to primate E. E-HP-¤ X174 complexes were prepared in vitro and infused into the circulation of mice under conditions allowing short term survival of E in the circulation. By radioimmunoassays and flow cytometry, we found that ¤ X174 is removed from E and cleared from the circulation coincident with loss of HP and CR1, and that the majority of cleared ¤ X174 is localized to the liver. Through the use of HP constructed with Fab' fragments, we verified the requirement for the Fc portion of the mAb in clearance; inhibition of C3 activation delayed clearance , suggesting a role for complement. The present findings in the mouse confirm previous observations in the non-human primate model.

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Immune Complexes Bound to the Primate Erythrocyte Complement Receptor (CR1) via Anti-CR1 Mabs Are Cleared Simultaneously with Loss of CR1 in a Concerted Reaction in a Rhesus Monkey Model

Cited by 39 publications

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Clearance of anti-double-stranded DNA antibodies: The natural immune complex clearance mechanism

Clearance of anti-double-stranded DNA antibodies: The natural immune complex clearance mechanism

Transfer of Immune Complexes from Erythrocyte CR1 to Mouse Macrophages

A prototype pathogen boundex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody complexes is cleared to the liver in a mouse model

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