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Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration

Nature Medicine volume 10, pages 187–192 (2004)Cite this article

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 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 μg 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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Figure 1: Consequences of CpG-ODN treatment on spleen weight, microarchitecture and germinal centers.
Figure 2: Quantitative effects of CpG-ODN on splenocyte subpopulations.
Figure 3: Hepatotoxicity of CpG-ODN.
Figure 4: Attenuation of immunoglobulin class switching and absence of humoral immunity to PrP.

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Acknowledgements

We thank B. Odermatt, B. Padberg and P. Schwarz for help. This work is supported by grants of the Bundesamt für Bildung und Wissenschaft (EU) and the Swiss National Foundation to A.A. and R.Z., the US National Prion Research Program to A.A. and C.S., and the National Centre of Competence in Research on neural plasticity and repair to A.A. M.H. is supported by a generous educational grant from the Catello family and by the Verein zur Förderung des Akademischen Nachwuchses. M.P. was supported by a Ph.D. fellowship from the Zentrum für Neurowissenschaften Zürich and a scientific grant from the United Banks of Switzerland. C.S. was supported by National Institutes of Health grant K08-AI01802.

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Author notes

  1. Mathias Heikenwalder and Magdalini Polymenidou: These authors contributed equally to this work.

Authors and Affiliations

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

    Mathias Heikenwalder, Magdalini Polymenidou, Christina Sigurdson & Adriano Aguzzi

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

    Tobias Junt & Rolf Zinkernagel

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

    Hermann Wagner

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

    Shizuo Akira

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  1. Mathias Heikenwalder
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Correspondence to Adriano Aguzzi.

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Heikenwalder, M., Polymenidou, M., Junt, T. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 10, 187–192 (2004). https://doi.org/10.1038/nm987

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