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The mechanism of anti-CD20–mediated B cell depletion revealed by intravital imaging
Fabricio Montalvao, … , Nico Van Rooijen, Philippe Bousso
Fabricio Montalvao, … , Nico Van Rooijen, Philippe Bousso
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5098-5103. https://doi.org/10.1172/JCI70972.
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Brief Report Immunology

The mechanism of anti-CD20–mediated B cell depletion revealed by intravital imaging

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Abstract

Anti-CD20 Ab therapy has proven successful for treating B cell malignancies and a number of autoimmune diseases. However, how anti-CD20 Abs operate in vivo to mediate B cell depletion is not fully understood. In particular, the anatomical location, the type of effector cells, and the mechanism underlying anti-CD20 therapy remain uncertain. Here, we found that the liver is a major site for B cell depletion and that recirculation accounts for the decrease in B cell numbers observed in secondary lymphoid organs. Using intravital imaging, we established that, upon anti-CD20 treatment, Kupffer cells (KCs) mediate the abrupt arrest and subsequent engulfment of B cells circulating in the liver sinusoids. KCs were also effective in depleting malignant B cells in a model of spontaneous lymphoma. Our results identify Ab-dependent cellular phagocytosis by KCs as a primary mechanism of anti-CD20 therapy and provide an experimental framework for optimizing the efficacy of therapeutic Abs.

Authors

Fabricio Montalvao, Zacarias Garcia, Susanna Celli, Béatrice Breart, Jacques Deguine, Nico Van Rooijen, Philippe Bousso

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Figure 3

KCs mediate the arrest and engulfment of normal and malignant B cells during anti-CD20 therapy.

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KCs mediate the arrest and engulfment of normal and malignant B cells du...
(A–D) Rag2–/– MAFIA mice were adoptively transferred with dye-labeled B cells and subjected to intravital imaging of the liver. (A) Representative time-lapse images recorded before or immediately after anti-CD20 injection. B cells are indicated by white circles. (B) B cell behavior and contact with KCs before or after anti-CD20 injection. Each line represents an individual B cell, red squares represent the time period during which B cells are present in the imaging field without contacting KCs, and green squares indicate the time period during which B cells are associated with a KC. (C) Impaired B cell arrest in FcRγ–/– mice treated with anti-CD20. Rag2–/–FcRγ–/– mice were transferred with dye-labeled B cells and injected with anti-CD20. (D) Rag2–/– MAFIA mice were injected with a YFP-expressing B cell tumor line. Representative time-lapse images show that tumor cells were rapidly engulfed by KCs upon anti-CD20 injection. Engulfed B cell tumors are indicated by white circles. (E and F) KCs are effectors of anti-CD20 therapy in a model of spontaneously developing B cell lymphoma. Csfr1gfp/+Cd19cre/+Rosa26RFP/+Eμ-myc+/– mice were subjected to intravital imaging of the liver following anti-CD20 injection. (E) Representative time-lapse images showing the engulfment and subsequent digestion of RFP-expressing lymphoma cells by KCs. (F) Quantification of B cell engulfment by KCs following anti-CD20 therapy. Scale bar: 10 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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