The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy.
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.
Uchida
Junji
J
Department of Immunology, Box 3010, Room 353 Jones Building, Research Drive, Duke University Medical Center, Durham, NC 27710, USA.
Hamaguchi
Yasuhito
Y
Oliver
Julie A
JA
Ravetch
Jeffrey V
JV
Poe
Jonathan C
JC
Haas
Karen M
KM
Tedder
Thomas F
TF
D000818:Animals; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D010586:Phagocytes / Q000276:immunology*; D017452:Receptors, IgG / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology
D018951:Antigens, CD20; C485700:Fcgr3 protein, mouse; D017452:Receptors, IgG