Cargando…
High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain
The brain is often described as an “immune-privileged” organ due to the presence of the blood-brain-barrier (BBB), which limits the entry of immune cells. In general, intracranial injection of adeno-associated virus (AAV) is considered a relatively safe procedure. In this study, we discovered that A...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518493/ https://www.ncbi.nlm.nih.gov/pubmed/37753218 http://dx.doi.org/10.1016/j.omtm.2023.08.021 |
_version_ | 1785109526037397504 |
---|---|
author | Guo, Yaowei Chen, Junliang Ji, Wenyu Xu, Liang Xie, Yu He, Shu Lai, Chuying Hou, Kaiyu Li, Zeru Chen, Gong Wu, Zheng |
author_facet | Guo, Yaowei Chen, Junliang Ji, Wenyu Xu, Liang Xie, Yu He, Shu Lai, Chuying Hou, Kaiyu Li, Zeru Chen, Gong Wu, Zheng |
author_sort | Guo, Yaowei |
collection | PubMed |
description | The brain is often described as an “immune-privileged” organ due to the presence of the blood-brain-barrier (BBB), which limits the entry of immune cells. In general, intracranial injection of adeno-associated virus (AAV) is considered a relatively safe procedure. In this study, we discovered that AAV, a popular engineered viral vector for gene therapy, can disrupt the BBB and induce immune cell infiltration in a titer-dependent manner. First, our bulk RNA sequencing data revealed that injection of high-titer AAV significantly upregulated many genes involved in disrupting BBB integrity and antiviral adaptive immune responses. By using histologic analysis, we further demonstrated that the biological structure of the BBB was severely disrupted in the adult mouse brain. Meanwhile, we noticed abnormal leakage of blood components, including immune cells, within the brain parenchyma of high-titer AAV injected areas. Moreover, we identified that the majority of infiltrated immune cells were cytotoxic T lymphocytes (CTLs), which resulted in a massive loss of neurons at the site of AAV injection. In addition, antagonizing CTL function by administering antibodies significantly reduced neuronal toxicity induced by high-titer AAV. Collectively, our findings underscore potential severe side effects of intracranial injection of high-titer AAV, which might compromise proper data interpretation if unaware of. |
format | Online Article Text |
id | pubmed-10518493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-105184932023-09-26 High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain Guo, Yaowei Chen, Junliang Ji, Wenyu Xu, Liang Xie, Yu He, Shu Lai, Chuying Hou, Kaiyu Li, Zeru Chen, Gong Wu, Zheng Mol Ther Methods Clin Dev Original Article The brain is often described as an “immune-privileged” organ due to the presence of the blood-brain-barrier (BBB), which limits the entry of immune cells. In general, intracranial injection of adeno-associated virus (AAV) is considered a relatively safe procedure. In this study, we discovered that AAV, a popular engineered viral vector for gene therapy, can disrupt the BBB and induce immune cell infiltration in a titer-dependent manner. First, our bulk RNA sequencing data revealed that injection of high-titer AAV significantly upregulated many genes involved in disrupting BBB integrity and antiviral adaptive immune responses. By using histologic analysis, we further demonstrated that the biological structure of the BBB was severely disrupted in the adult mouse brain. Meanwhile, we noticed abnormal leakage of blood components, including immune cells, within the brain parenchyma of high-titer AAV injected areas. Moreover, we identified that the majority of infiltrated immune cells were cytotoxic T lymphocytes (CTLs), which resulted in a massive loss of neurons at the site of AAV injection. In addition, antagonizing CTL function by administering antibodies significantly reduced neuronal toxicity induced by high-titer AAV. Collectively, our findings underscore potential severe side effects of intracranial injection of high-titer AAV, which might compromise proper data interpretation if unaware of. American Society of Gene & Cell Therapy 2023-08-28 /pmc/articles/PMC10518493/ /pubmed/37753218 http://dx.doi.org/10.1016/j.omtm.2023.08.021 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Guo, Yaowei Chen, Junliang Ji, Wenyu Xu, Liang Xie, Yu He, Shu Lai, Chuying Hou, Kaiyu Li, Zeru Chen, Gong Wu, Zheng High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title | High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title_full | High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title_fullStr | High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title_full_unstemmed | High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title_short | High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
title_sort | high-titer aav disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518493/ https://www.ncbi.nlm.nih.gov/pubmed/37753218 http://dx.doi.org/10.1016/j.omtm.2023.08.021 |
work_keys_str_mv | AT guoyaowei hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT chenjunliang hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT jiwenyu hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT xuliang hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT xieyu hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT heshu hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT laichuying hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT houkaiyu hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT lizeru hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT chengong hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain AT wuzheng hightiteraavdisruptscerebrovascularintegrityandinduceslymphocyteinfiltrationinadultmousebrain |