The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy

• Published in: The Journal of experimental medicine Vol. 199; no. 12; pp. 1659 - 1669
• Main Authors: Uchida, Junji, Hamaguchi, Yasuhito, Oliver, Julie A, Ravetch, Jeffrey V, Poe, Jonathan C, Haas, Karen M, Tedder, Thomas F
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 21-06-2004
• Subjects: Animals; Antigens, CD20 - genetics; Antigens, CD20 - immunology; B-Lymphocytes - immunology; Immunotherapy - methods; Leukocytes, Mononuclear - immunology; Lymphocyte Depletion; Mice; Mice, Knockout; Phagocytes - immunology; Receptors, IgG - blood; Receptors, IgG - deficiency; Receptors, IgG - genetics; Receptors, IgG - immunology; Spleen - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20040119

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 FcgammaRI- and FcgammaRIII-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 FcgammaR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.