title: Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
abstract: B cell immunotherapy has emerged as a mainstay in the treatment of lymphomas and autoimmune diseases. Although the microenvironment has recently been demonstrated to play critical roles in B cell homeostasis, its contribution to immunotherapy is unknown. To analyze the in vivo factors that regulate mechanisms involved in B cell immunotherapy, we used a murine model for human CD20 (hCD20) expression in which treatment of hCD20(+) mice with anti-hCD20 mAbs mimics B cell depletion observed in humans. We demonstrate in this study that factors derived from the microenvironment, including signals from the B cell-activating factor belonging to the TNF family/BLyS survival factor, integrin-regulated homeostasis, and circulatory dynamics of B cells define distinct in vivo mechanism(s) and sensitivities of cells in anti-hCD20 mAb-directed therapies. These findings provide new insights into the mechanisms of immunotherapy and define new opportunities in the treatment of cancers and autoimmune diseases.
authors.affiliation: Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gong
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Ou
authors.forename: Shiming
authors.initials: S
authors.lastname: Ye
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Jennine
authors.initials: J
authors.lastname: Cornelius
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Wei Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Zhilan
authors.initials: Z
authors.lastname: Hu
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lu
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Peter
authors.initials: P
authors.lastname: Gribling
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Kathy
authors.initials: K
authors.lastname: Nguyen
authors.forename: Thanhvien
authors.initials: T
authors.lastname: Tran
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood; D018951:Antigens, CD20 / Q000097:blood / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000502:physiology; D004198:Disease Susceptibility / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008099:Liver / Q000166:cytology / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000166:cytology / Q000276:immunology; D012157:Mononuclear Phagocyte System / Q000166:cytology / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D003165:Complement System Proteins