Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
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.
Gong
Qian
Q
Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Ou
Qinglin
Q
Ye
Shiming
S
Lee
Wyne P
WP
Cornelius
Jennine
J
Diehl
Lauri
L
Lin
Wei Yu
WY
Hu
Zhilan
Z
Lu
Yanmei
Y
Chen
Yongmei
Y
Wu
Yan
Y
Meng
Y Gloria
YG
Gribling
Peter
P
Lin
Zhonghua
Z
Nguyen
Kathy
K
Tran
Thanhvien
T
Zhang
Yifan
Y
Rosen
Hugh
H
Martin
Flavius
F
Chan
Andrew C
AC
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
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D003165:Complement System Proteins