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Letter
Nature Medicine  10, 187 - 192 (2004)
Published online: 25 January 2004; | doi:10.1038/nm987

Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration

Mathias Heikenwalder1, 5, Magdalini Polymenidou1, 5, Tobias Junt2, Christina Sigurdson1, Hermann Wagner3, Shizuo Akira4, Rolf Zinkernagel2 & Adriano Aguzzi1

1  Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.

2  Institute of Experimental Immunology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.

3  Institute for Medical Microbiology, Immunology and Hygiene, University of Munich, Trogerstrasse 9, D-81675 Munich, Germany.

4  Department of Host Defense, Research Institute for Microbiological Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

5  These authors contributed equally to this work.

Correspondence should be addressed to Adriano Aguzzi adriano@pathol.unizh.ch
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 cells1, and activates a pathway involving Toll-like receptor-9 (TLR9)2. 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 mug 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 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.


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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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