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Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like Receptor-9-Mediated Activation of Adaptive Immunity

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Abstract

Purpose

This paper aims to investigate the immunoinhibitory properties of a lymph nodes-targeting suppressive oligonucleotide (ODN) for the potential treatment of autoimmune diseases or chronic inflammation.

Methods

Synthetic suppressive ODN engineered with an albumin-binding diacyl lipid at the 5′-terminal (lipo-ODN) was synthesized. In vitro and in vivo experiments were designed to compare the immune suppressive properties of lipo-ODN and unmodified ODN. Cellular uptake and distribution, inhibition of Toll-like receptor (TLR) activation, lymph nodes (LN) draining, and the suppression of antigen-specific immune responses in an ovalbumin protein model was investigated.

Results

Compared to unmodified ODN, lipid functionalized suppressive ODN demonstrated enhanced cellular uptake and TLR-9 specific immune suppression in TLR reporter cells. Additionally, injection of a low dose of lipid-modified suppressive ODN, but not the unconjugated ODN, accumulated in the draining LNs and exhibited potent inhibition of antigen-specific CD8+ T cell and B cell responses in vivo.

Conclusions

Targeting suppressive ODN to antigen presenting cells (APCs) in the local LNs is an effective approach to amplify the immune modulation mediated by ODN containing repetitive TTAGGG motif. This approach might be broadly applicable to target molecular adjuvants to the key immune cells in the LNs draining from disease site, providing a simple strategy to improve the efficacy of many molecular immune modulators.

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Abbreviations

BSA:

Bovine serum albumin

CpG ODN:

CpG oligodeoxynucleotides

DAPI:

4′,6-diamidino-2-phenylindole

DC 2.4:

Dendritic cell 2.4

ELISA:

Enzyme-linked immunosorbent assay

FAM:

Fluorescein amidite

IgG:

Immunoglobulin G

LN:

Lymph node

LPS:

Lipopolysaccharide

MHC:

Major histocompatibility complex

OVA:

Ovalbumin

PBS:

Phosphate buffered saline

SEAP:

Secreted embryonic alkaline phosphatase

Sup-ODN:

Suppressive oligodeoxynucleotides

TLR-9:

Toll-like receptor 9

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Author information

Authors and Affiliations

  1. Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan, 48202, USA

    Chunsong Yu, Myunggi An & Haipeng Liu

  2. Department of Chemistry, Wayne State University, Detroit, Michigan, 48202, USA

    Evan Jones

  3. Department of Oncology, Wayne State University, Detroit, Michigan, 48201, USA

    Haipeng Liu

  4. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, 48201, USA

    Haipeng Liu

Authors
  1. Chunsong Yu
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  2. Myunggi An
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  3. Evan Jones
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  4. Haipeng Liu
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Correspondence to Haipeng Liu.

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Yu, C., An, M., Jones, E. et al. Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like Receptor-9-Mediated Activation of Adaptive Immunity. Pharm Res 35, 56 (2018). https://doi.org/10.1007/s11095-018-2344-2

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  • DOI: https://doi.org/10.1007/s11095-018-2344-2

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