[Molecular mechanisms of B lymphocyte depletion by CD20 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 and the in vivo effect of immunotherapy on tissue B cells and their subsets is generally unknown. 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. 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 utilized FcgammaRI-, FcgammaRIII- and FcgammaRIV-dependent pathways, while 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 NK cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3 complement components. The considerable factors that determine the effectiveness of anti-CD20 immunotherapy are following: the expression level of CD20 on B cell surface; the dosage of anti-CD20 mAb; the association of Fcgamma receptor with the isotype of the antibies; B cell subpopulations within different tissues. These findings have important clinical implications for anti-CD20 and other antibody-based therapies.
Hamaguchi
Yasuhito
Y
Department of Dermatology, Kanazawa University Graduate School of Medical Science.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy; D001402:B-Lymphocytes / Q000276:immunology*; D007167:Immunotherapy; D008212:Lymphocyte Depletion; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D051379:Mice; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D017452:Receptors, IgG; D000069283:Rituximab