Induction of immune tolerance to FIX by intramuscular AAV gene transfer is independent of the activation status of dendritic cells

Bharadwaj, Arpita; Kelly, Meagan; Kim, Dong-Soo; Chao, Hengjun

doi:10.1182/blood-2009-08-239509

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…injection. 27 Collectively, these studies suggest that AAV2 avoids upregulation of the molecules critical for T cell priming, including signal 1 (MHCI/II), signal 2 (CD80/86), and signal 3 (inflammatory cytokines). A recent report indicated that adaptive immunity to AAV1, 2, and 9 vectors was dependent upon innate immune activation through the TLR9/MyD88 pathway to stimulate type I IFNs.…”

Section: Upstream: Ineffective T Cell Priming Is the Results Of Poor Apc Transduction And Activation By Aav8mentioning

confidence: 95%

“…These data support previous findings that AAV2 vectors show poor upregulation of MHCII or CD80/86 on the surface of CD11c + DCs. 27 Limited MHCII upregulation may prevent priming of CD4 + T helper cells, which have been shown to play a critical role in CD8 + T cell activation, effecting either initial CD8 priming, or the establishment of functional CD8 memory. This is supported by our previous findings that AAV2/8 shows minimal CD4 + infiltration in comparison with AAV2/rh32.33.…”

Section: Discussionmentioning

confidence: 99%

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AAV8 Induces Tolerance in Murine Muscle as a Result of Poor APC Transduction, T Cell Exhaustion, and Minimal MHCI Upregulation on Target Cells

et al. 2014

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Following gene transfer of adeno-associated virus 2/8 (AAV2/8) to the muscle, C57BL/6 mice show long-term expression of a nuclear-targeted LacZ (nLacZ) transgene with minimal immune activation. Here, we show that pre-exposure to AAV2/8 can also induce tolerance to the more immunogenic AAV2/rh32.33 vector, preventing otherwise robust T-cell activation and allowing stable transgene expression. Depletion and adoptive transfer studies showed that a suppressive factor was not sufficient to account for AAV2/8-induced tolerance, whereas further characterization of the T-cell population showed upregulation of the exhaustion markers PD1, 2B4, and LAG3. Furthermore, systemic administration of Toll-like receptor (TLR) ligands at the time of AAV2/rh32.33-administration broke AAV2/8-induced tolerance, restoring T-cell activation and β-gal clearance. As such, AAV2/8 transduction appears to lack the inflammatory signals necessary to prime a functional cytotoxic T-cell response. Inadequate T-cell priming could be explained upstream by AAV2/8's poor transduction and activation of antigen-presenting cells (APCs). Immunohistochemical analysis indicates that AAV2/8 transduction also fails to upregulate major histocompatibility complex class I (MHCI) expression on the surface of myocytes, rendering transduced cells poor targets for T-cell-mediated destruction. Overall, AAV2/8-induced tolerance in the muscle is multifactorial, spanning from poor APC transduction and activation to the subsequent priming of functionally exhausted T-cells, while simultaneously avoiding upregulation of MHCI on potential targets.

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Section: Upstream: Ineffective T Cell Priming Is the Results Of Poor Apc Transduction And Activation By Aav8mentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

AAV8 Induces Tolerance in Murine Muscle as a Result of Poor APC Transduction, T Cell Exhaustion, and Minimal MHCI Upregulation on Target Cells

et al. 2014

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“…injections of high concentrations of AAV may actually lead to the induction of immune tolerance. 23,24 Indeed, when we examined for humoral-or cell-mediated immune responses, we found that mice p.o. vaccinated with either AAV5-neu or AAV6-neu demonstrated significantly higher levels of circulating anti-NEU antibodies and stronger antitumor CTL responses compared with those receiving the i.m.…”

Section: Discussionmentioning

confidence: 99%

Oral Vaccination With Adeno-associated Virus Vectors Expressing the Neu Oncogene Inhibits the Growth of Murine Breast Cancer

et al. 2013

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Recombinant adeno-associated viruses (AAV) have been used for therapeutic gene transfer. These vectors offer a number of advantages including resistance to the effects of pH, a broad cellular tropism, efficient gene transfer, persistence of gene expression, and little toxicity. AAV vectors; however, at high doses can induce humoral and cellular immune responses. While potentially problematic for replacement gene therapy, this effect may be advantageous for antitumor vaccination. We examined the activity of an oral and intramuscular antitumor vaccination using AAV serotypes 5 and 6 expressing a truncated neu oncogene in a neu-positive murine TUBO breast cancer model. Mice receiving a single oral administration of AAV5-neu or AAV6-neu demonstrated improved survival. Oral vaccination significantly improved survivals compared with intramuscular vaccination. Mice vaccinated with AAV6-neu survived longer than those treated with AAV5-neu. Vaccination with AAV5-neu or AAV6-neu induced both humoral and cellular immune responses against the NEU antigen. These responses were more robust in the mice undergoing oral vaccination compared with mice receiving the intramuscular vaccination. Protection from tumor was long lasting with 80% of the animals treated with oral AAV6-neu surviving a re-challenge with TUBO cells at 120 and 320 days post-vaccination. Further evaluation of AAV-based vectors as tumor vaccines is warranted.

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“…Mature DC cells can effectively activate initial T cells and are at the center of initiating, regulating, and maintaining immune responses. Under stimulation by inflammatory, DCs were activated to initiate and promoted immunity ( Bharadwaj et al, 2010 ). In the field of tumor immunotherapy research, the six immune checkpoints PDCD1, CD274, CTLA-4, LAG-3, TIGIT, and HAVCR2 can inhibit the proliferation, activation and effector functions of T cells, and maintain the immune homeostasis in the body.…”

Section: Discussionmentioning

confidence: 99%

High LYRM4-AS1 predicts poor prognosis in patients with glioma and correlates with immune infiltration

Wang,

Xie,

et al. 2023

PeerJ

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Background Many researches proved that non-coding RNAs are important in glioma development. We screened the differentially expressed genes through The Cancer Genome Atlas (TCGA) database and identified the molecule LYRM4-AS1 associated with prognosis. As a lncRNA, the expression level and role of LYRM4-AS1 in glioma are inconclusive. Therefore, we attempted to assess the clinical significance, expression and related mechanisms of LYRM4-AS1 in glioma by employing cell experiments and an integrative in silico methodology. Methods RNA-seq data were obtained from UCSC XENA and TCGA datasets. The Gene Expression Omnibus (GEO) database was used to download glioma-related expression profile data. The LYRM4-AS1 expression level was evaluated. Survival curves were constructed by the Kaplan–Meier method. Cox regression analysis was used to analyze independent variables. Patients were divided into high and low expression group base on the median LYRM4-AS1 expression value in glioma tissues. The DESeq2 R package was used to identify differentially expressed genes (DEGs) between two different expression LYRM4-AS1 groups. Gene set enrichment analysis (GSEA) was conducted. Next, the single-sample Gene Set Enrichment Analysis (ssGSEA) was done to quantify the immune infiltration of immune cells in glioma tissues. Gene expression profiles for glioma tumor tissues were used to quantify the relative enrichment score for each immune cell. Spearman correlation analysis was used to analyze the correlation between LYRM4-AS1 and biomarkers of immune cells as well as immune checkpoints in glioma. Finally, assays for cell apoptosis, cell viability and wound healing were conducted to evaluate the function on U87 MG and U251 cells after knocking down LYRM4-AS1. Results We found that LYRM4-AS1 was upregulated and related to the grade and malignancy of glioma. Survival analyses showed that high expression LYRM4-AS1 patients had poor clinical outcomes (P < 0.01). Cox regression analyses demonstrated that LYRM4-AS1 was an independent risk factor for overall survival (OS) in glioma (HR: 274 1.836; CI [1.278–2.639]; P = 0.001). Enrichment and immune infiltration analysis showed interferon signaling and cytokine-cytokine receptor interaction enriched in the LYRM4-AS1 high-expression phenotype, and LYRM4-AS1 showed significantly positively related to immune infiltration as well as immune checkpoints (P < 0.01). The knockdown of LYRM4-AS1 in U87 MG and U251 cells can inhibit migration and proliferation of cells (P < 0.05). Conclusions These findings indicated that the increased LYRM4-AS1 may be useful for the diagnosis and prognosis of glioma and might participate in the immune infiltration.

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Induction of immune tolerance to FIX by intramuscular AAV gene transfer is independent of the activation status of dendritic cells

Cited by 5 publications

References 26 publications

AAV8 Induces Tolerance in Murine Muscle as a Result of Poor APC Transduction, T Cell Exhaustion, and Minimal MHCI Upregulation on Target Cells

AAV8 Induces Tolerance in Murine Muscle as a Result of Poor APC Transduction, T Cell Exhaustion, and Minimal MHCI Upregulation on Target Cells

Oral Vaccination With Adeno-associated Virus Vectors Expressing the Neu Oncogene Inhibits the Growth of Murine Breast Cancer

High LYRM4-AS1 predicts poor prognosis in patients with glioma and correlates with immune infiltration

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