Cited by 39Virus-based gene therapy researchImmunotherapy and Immune ResponsesRNA Interference and Gene Delivery

Regulatory T cells and TLR9 activation shape antibody formation to a secreted transgene product in AAV muscle gene transfer

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Herzog, Roland W., Cooper, Mario, Perrin, George Q., Biswas, Moanaro, Martino, Ashley T., Morel, Laurence, Terhorst, Cox, Hoffman, Brad E.·2019·Cellular Immunology

Abstract

Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response. ODN activated monocyte-derived dendritic cells and enhanced T follicular helper cell responses. While depletion of regulatory T cells (Tregs) also caused an antibody response, TLR9 activation combined with Treg depletion instead resulted in prolonged CD8+ T cell infiltration of transduced muscle. Thus, Tregs modulate the response to the TLR9 agonist. Further, Treg re-population eventually resolved humoral and cellular immune responses. Therefore, specific modes of TLR9 activation and Tregs orchestrate antibody formation in muscle gene transfer.

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Authors
Herzog, R. W., Cooper, M., Perrin, G. Q., Biswas, M., Martino, A. T., Morel, L., Terhorst, C., & Hoffman, B. E.
Affiliations
  • University of Florida Health (US)
  • University of Florida (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
  • Herzog, Roland W.
  • Hoffman, Brad E.
Venue
Cellular Immunology
Publisher
Elsevier BV
Published
2019-08
Volume
342
Pages
103682
ISSN
0008-8749 (ISSN-L)
OpenAlex
W2739915030
Cited by
39
References
55
Citations by year
2026: 2 · 2025: 3 · 2024: 7 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 2
FWCI
1.63
Type
journal article
Language
en
Open access
Locations
  • Cellular Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Pfizer
  • National Institutes of Health (R01 HL131093, R01 AI51390)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
regulatory T cells, TLR9 activation, CpG oligodeoxynucleotides, adeno-associated virus, AAV gene transfer, skeletal muscle, coagulation factor IX, antibody response, T follicular helper cells, dendritic cells, CD8+ T cell infiltration, immune tolerance
MeSH terms
Dependovirus, Animals, Antibody Formation, Factor IX, Male, Mice, Inbred C57BL, Oligodeoxyribonucleotides, Gene Transfer Techniques, Muscle, Skeletal, Transgenes, T-Lymphocytes, Regulatory, Toll-Like Receptor 9, Mice

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