The Journal of Experimental Medicine
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Published 21 June 2004. doi:10.1084/jem.20040119
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1659-1669
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The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

Junji Uchida1, Yasuhito Hamaguchi1, Julie A. Oliver1, Jeffrey V. Ravetch2, Jonathan C. Poe1, Karen M. Haas1, and Thomas F. Tedder1

1 Department of Immunology, Duke University Medical Center, Durham, NC 27710
2 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021

Address correspondence to Thomas F. Tedder, Department of Immunology, Box 3010, Room 353 Jones Building, Research Drive, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-3578; Fax: (919) 684-8982; email: thomas.tedder{at}duke.edu

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both Fc{gamma}RI- and Fc{gamma}RIII-dependent pathways, whereas B cells were not eliminated in FcR common {gamma} chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through Fc{gamma}R-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

Key Words: lymphoma • therapy • autoimmune diseases • mouse model • Rituximab

J. Uchida and Y. Hamaguchi contributed equally to this work.

Abbreviation used in this paper: PI, propidium iodide.


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