title: Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration.
abstract: DNA containing unmethylated cytidyl guanosyl (CpG) sequences, which are underrepresented in mammalian genomes but prevalent in prokaryotes, is endocytosed by cells of the innate immune system, including macrophages, monocytes and dendritic cells, and activates a pathway involving Toll-like receptor-9 (TLR9). CpG-containing oligodeoxynucleotides (CpG-ODN) are potent stimulators of innate immunity, and are currently being tested as adjuvants of antimicrobial, antiallergic, anticancer and antiprion immunotherapy. Little is known, however, about the consequences of repeated CpG-ODN administration, which is advocated for some of these applications. Here we report that daily injection of 60 microg CpG-ODN dramatically alters the morphology and functionality of mouse lymphoid organs. By day 7, lymphoid follicles were poorly defined; follicular dendritic cells (FDC) and germinal center B lymphocytes were suppressed. Accordingly, CpG-ODN treatment for > or =7 d strongly reduced primary humoral immune responses and immunoglobulin class switching. By day 20, mice developed multifocal liver necrosis and hemorrhagic ascites. All untoward effects were strictly dependent on CpG and TLR9, as neither the CpG-ODN treatment of Tlr9(-/-) mice nor the repetitive challenge of wild-type mice with nonstimulatory ODN (AT-ODN) or with the TLR3 agonist polyinosinic:cytidylic acid (polyI:C) were immunotoxic or hepatotoxic.
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Magdalini
authors.initials: M
authors.lastname: Polymenidou
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.forename: Christina
authors.initials: C
authors.lastname: Sigurdson
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Rolf
authors.initials: R
authors.lastname: Zinkernagel
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018899:CpG Islands; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D007165:Immunosuppression Therapy; D008221:Lymphoid Tissue / Q000033:anatomy & histology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000378:metabolism*; D009929:Organ Size; D011328:Prions / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051217:Toll-Like Receptor 9
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; C408982:CPG-oligonucleotide; D016207:Cytokines; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D009838:Oligodeoxyribonucleotides; D011328:Prions; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9