Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells
Open accessAbstract
Background Gene and protein replacement therapies for inherited protein deficiencies such as hemophilia or lysosomal storage disorders are limited by deleterious immune responses directed against their respective therapeutic proteins. Therefore, the development of protocols preventing such responses is key to providing successful long-term therapy.Objectives We sought to develop a protocol, utilizing a drug/peptide cocktail, that would effectively shift the antigen-specific CD4+ T-cell population, tipping the balance from effector T cells (Teffs) towards regulatory T cells (Tregs).Methods Treg-deficient (DO11.10-tg Rag2(-/-)) BALB/c mice were used to screen for an optimal protocol addressing the aforementioned goal and to study the mechanisms underlying in vivo changes in T-cell populations. Muscle-directed gene transfer to hemophilia B mice was also performed in order to test the optimal protocol in a therapeutically relevant setting.Results Specific antigen administration (4-week repeated dosing) combined with rapamycin and interleukin-10 led to substantial reductions in Teffs, via activation-induced cell death, and induced CD4+CD25+FoxP3+ Tregs to a large extent in multiple organs. The proportion of apoptotic T cells also increased over time, whereas Teffs and Tregs were differentially affected. When applied to a model of protein deficiency (gene therapy for hemophilia B), the protocol successfully prevented inhibitor formation, whereas non-specific immunosuppression was only marginally effective.Conclusions It is feasible to provide a short-term, prophylactic protocol allowing for the induction of immune tolerance. This protocol may provide a marked advance in efforts seeking to improve clinical outcomes in disorders involving therapeutic protein replacement.
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Increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction.
“However, the exact opposite is true, and increased levels of gene expression resulting from higher vector doses promote immune tolerance through elevated expression of the immune suppressive cytokine IL-10, enhanced apoptosis of effector T cells, and enhanced Treg induction similar to that observed with a very high HBV inoculum in chimpanzees.15,56,57,58,59,60,61,62”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [60]
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Self-citation
- Authors
- NAYAK, S., CAO, O., HOFFMAN, B. E., COOPER, M., ZHOU, S., ATKINSON, M. A., & HERZOG, R. W.
- Affiliations
- University of Florida (US)
- Children's Hospital of Philadelphia (US)
- University of Florida Health (US)
- Corresponding author
- HERZOG, R.W.
- Venue
- Journal of Thrombosis and Haemostasis
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 7
- Issue
- 9
- Pages
- 1523-1532
- ISSN
- 1538-7836 (ISSN-L)
- PMC
- PMC2981868
- OpenAlex
- W2029392819
- Cited by
- 66
- References
- 21
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 3 · 2022: 3 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 9 · 2013: 4 · 2012: 6
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL078810)
- National Institute of Allergy and Infectious Diseases (R01 AI/HL51390, R01AI051390)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK074367)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD051390)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune tolerance, regulatory T cells, effector T cells, rapamycin, IL-10, hemophilia B, gene therapy, inhibitor formation, activation-induced cell death, CD4+ T cells, Foxp3, lysosomal storage disease
- MeSH terms
- Animals, Antigens, Factor IX, Hemophilia A, Humans, Immune Tolerance, Mice, Inbred BALB C, Mice, Inbred C3H, Genetic Therapy, CD4-Positive T-Lymphocytes, Interleukin-10, Sirolimus, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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