B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model.
We report the development of a mouse B cell-depleting immunoconjugate (anti-CD22 monoclonal antibody [mAb] conjugated to calicheamicin) and its in vivo use to characterize the kinetics of CD22+ B-cell depletion and reconstitution in murine primary and secondary lymphoid tissues. The effect of B-cell depletion was further studied in a murine collagen-induced arthritis (CIA) model and a respiratory syncytial virus (RSV) vaccination model. Our results show that (1) the immunoconjugate has B-cell-specific in vitro and in vivo cytotoxicity; (2) B-cell reconstitution starts in the bone marrow and spleen around day 30 after depletion and is completed in all tissues tested by day 50; (3) B-cell depletion inhibits the development of clinical and histologic arthritis in the CIA model; (4) depletion of type II collagen antibody levels is not necessary for clinical and histologic prevention of CIA; and (5) B-cell depletion does not adversely affect memory antibody responses after challenge nor clearance of infectious virus from lungs in the RSV vaccination model. These results demonstrate for the first time that only B-cell reduction but not type II collagen antibody levels correlate with the prevention of arthritis and represent key insights into the role of CD22-targeted B-cell depletion in mouse autoimmunity and vaccination models.
Dunussi-Joannopoulos
Kyri
K
Department of Inflammation, Wyeth Research, Cambridge, MA, USA. kdunussi@wyeth.com
Hancock
Gerald E
GE
Kunz
Arthur
A
Hegen
Martin
M
Zhou
Xiaochuan X
XX
Sheppard
Barbara J
BJ
Lamothe
Jennifer
J
Li
Evelyn
E
Ma
Hak-Ling
HL
Hamann
Philip R
PR
Damle
Nitin K
NK
Collins
Mary
M
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000628:therapy*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D049109:Cell Proliferation; D024043:Collagen Type II / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000097:blood; D007156:Immunologic Memory; D007249:Inflammation; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism; D022261:Respiratory Syncytial Virus Vaccines; D012136:Respiratory Syncytial Viruses / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology; D013997:Time Factors
D024043:Collagen Type II; D007075:Immunoglobulin M; D022261:Respiratory Syncytial Virus Vaccines