Visualization of the Transfer Reaction: Tracking Immune Complexes from Erythrocyte Complement Receptor 1 to Macrophages

Craig, Maria; Bankovich, Alexander J.; Taylor, Ronald P.

doi:10.1006/clim.2002.5266

Cited by 31 publications

(30 citation statements)

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confidence: 99%

“…29,30 In addition, CR1 plays a role in the clearance of immune complexes and in phagocytosis. [31][32][33] Thus, the lower levels of CR1 expression on the red cell surface associated with the H/L and L/L genotypes 22 are expected to result in increased complement activation and C3 binding on PNH red cells.In order to test this hypothesis we investigated the kinetics of C3 binding to GPI-negative red cells in vitro 13,14 from patients with the three CR1 HindIII genotypes. When GPI-negative red cells were exposed to activated complement in the presence of eculizumab, we promptly detected C3-positive PNH red cells, the percentage of which increased with time.…”

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Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nphic alleles of the C3 gene and of the complement receptor 1 (CR1) gene. Methods PatientsSeventy-two patients with hemolytic PNH who had received eculizumab treatment were analyzed after a median follow-up of 52 months (range, 11-98 months). Patients with evidence of bone marrow failure (reticulocytes ≤60x10 9 /L, platelets ≤50x10 9 /L, neutrophils ≤1x10 9 /L) were not included in this series because this condition may affect the clinical response to eculizumab regardless of how well hemolysis is controlled. Peripheral blood samples were collected for clinical testing, flow cytometry (GPI-molecules and C3-binding) 7 and genotyping after the patients had signed an informed consent form approved by the respective Institutional Review Board. As a criterion of response to eculizumab we used the one that is most stringent and objective: namely RBC transfusion at any time after the first 6 months on eculizumab treatment. Of the 72 patients 60 were transfusiondependent before eculizumab: of these 60, those who on eculizumab received no further transfusion during follow-up have been classified as good responders; those who on eculizumab received one or more RBC transfusion at any time during follow-up have been classified as suboptimal responders. Twelve patients started eculizumab before having received any RBC transfusions. Of these, the ten patients who on eculizumab remained transfusion-independent have been classified as good responders because their hemoglobin level increased, on average, by 2.2 g/dL; the remaining two patients required RBC transfusions on eculizumab and have been classified as sub-optimal responders. Only one patient, who had hemolytic PNH at the time of starting eculizumab and who had already been classified as a sub-optimal responder, became aplastic during follow-up. GenotypingThe polymorphism rs2230199 C>G of the C3 gene was investigated by a newly designed tetra-primer amplification refractory mutation system-polymerase chain reaction method.11 Three polymorphisms of the CR1 gene were genotyped by restriction fragment length (RFLP) analysis:12 HindIII RFLP (intron 27); His1208Arg (exon 22); Pro1827Arg (exon 33). Kinetics of C3 binding in vitroRBC and sera were promptly separated from peripheral blood freshly collected from PNH patients. The RBC were then incubated with sera containing eculizumab as previously described. 13,14 Briefly, a 2% suspension of RBC from PNH patients was incubated at 37°C with a pool of ABO-compatible sera from patients on eculizumab, and the complement alternative pathway was activated by mild acidification (HCl 0.016 M). At serial time points (15,30, 60, and 120 min) after complement activation the fraction of GPI-negative RBC with newly bound C3 fragments was measured by flow cytometry (AccuriC6, Becton Dickinson, NJ, USA) after staining with anti-CD59 Alexa647 (Mem43, Serotec, UK) and anti-C3d-neoantigen (A250, Quidel, CA, USA); secondary staining was performed with phycoerythrin-labeled polyclonal rabbit-an...

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Section: © F E R R a T A S T O R T I F O U N D A T I O N Among Those mentioning

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Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

et al. 2013

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“…CD20 ϩ Raji and ARH 77 cells, and THP-1 cells were obtained from American Type Culture Collection and maintained as described previously (34,39,40). CD20 ϩ Z138 mantle cell lymphoma cells (41) were cultured in RPMI 1640 with 10% heat-inactivated FBS, 100 U/ml penicillin, 100 g/ml streptomycin, and 2 mM glutamine.…”

Section: Cellsmentioning

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

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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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“…University of Virginia Institutional Review Board approved all protocols. Monocytes were isolated from PBMC by allowing them to adhere to tissue culture plastic (47,48) and the purity of different preparations varied between 60 and 90%, based on staining for CD11b and CD14 (46). NK cells were isolated from PBMC using CD56 microbeads or a negative selection protocol followed by purification using an AutoMACS magnetic cell separator, according to the manufacturer's directions (Miltenyi Biotec).…”

Section: Cellsmentioning

confidence: 99%

Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving

Beum

Lindorfer

Taylor

2008

The Journal of Immunology

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Treatment of chronic lymphocytic leukemia patients with anti-CD20 mAb rituximab (RTX) leads to substantial CD20 loss on circulating malignant B cells soon after completion of the RTX infusion. This CD20 loss, which we term shaving, can compromise the therapeutic efficacy of RTX, and in vitro models reveal that shaving is mediated by effector cells which express FcγRI. THP-1 monocytes and PBMC promote shaving, but PBMC also kill antibody-opsonized cells by antibody-dependent cellular cytotoxicity (ADCC), a reaction generally considered to be due to NK cells. We hypothesized that within PBMC, monocytes and NK cells would have substantially different and competing activities with respect ADCC or shaving, thereby either enhancing or inhibiting the therapeutic action of RTX. We measured ADCC and RTX removal from RTX-opsonized Daudi cells promoted by PBMC, or mediated by NK cells and monocytes. NK cells take up RTX and CD20 from RTX-opsonized B cells, and mediate ADCC. PBMC depleted of NK cells show little ADCC activity, whereas PBMC depleted of monocytes have greater ADCC than the PBMC. Pre-treatment of RTX-opsonized B cells with THP-1 cells or monocytes suppresses NK cell-mediated ADCC, and blockade of FcγRI on monocytes or THP-1 cells abrogates their ability to suppress ADCC. Our results indicate NK cells are the principal cells in PBMC that kill RTX-opsonized B cells, and that monocytes can suppress ADCC by promoting shaving. These results suggest that RTX-based immunotherapy of cancer may be enhanced based on paradigms which include infusion of compatible NK cells and inhibition of monocyte shaving activity.

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Visualization of the Transfer Reaction: Tracking Immune Complexes from Erythrocyte Complement Receptor 1 to Macrophages

Cited by 31 publications

References 44 publications

Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

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

Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving

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