Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.

We have recently demonstrated that adeno-associated virus serotype 9 (AAV9)-mediated human erythropoietin (hEPO) gene delivery into the brain protects dopaminergic (DA) neurons in the substantia nigra in a rat model of Parkinson's disease. In the present study, we examined whether pre-exposure...

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Main Authors: Chun Yang, Wei-Hua Yang, Sha-Sha Chen, Bao-Feng Ma, Bin Li, Tao Lu, Ting-Yu Qu, Ronald L Klein, Li-Ru Zhao, Wei-Ming Duan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3648480?pdf=render
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spelling doaj-6ddcd4fa776b487da9a369bad7b4a3982020-11-24T21:51:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6387610.1371/journal.pone.0063876Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.Chun YangWei-Hua YangSha-Sha ChenBao-Feng MaBin LiTao LuTing-Yu QuRonald L KleinLi-Ru ZhaoWei-Ming DuanWe have recently demonstrated that adeno-associated virus serotype 9 (AAV9)-mediated human erythropoietin (hEPO) gene delivery into the brain protects dopaminergic (DA) neurons in the substantia nigra in a rat model of Parkinson's disease. In the present study, we examined whether pre-exposure to AAV9-hEPO vectors with an intramuscular or intrastriatal injection would reduce AAV9-mediated hEPO transduction in rat brain. We first characterized transgene expression and immune responses against AAV9-hEPO vectors in rat striatum at 4 days, 3 weeks and 6 months, and with doses ranging from 10(11) to 10(13) viral genomes. To sensitize immune system, rats received an injection of AAV9-hEPO into either the muscle or the left striatum, and then sequentially an injection of AAV9-hEPO into the right striatum 3 weeks later. We observed that transgene expression exhibited in a time course and dose dependent manner, and inflammatory and immune responses displayed in a time course manner. Intramuscular, but not intrastriatal injections of AAV9-hEPO resulted in reduced levels of hEPO transduction and increased levels of the major histocompatibility complex (MHC) class I and class II antigen expression in the striatum following AAV9-hEPO re-administration. There were infiltration of the cluster of differentiation 4 (CD4)-and CD8-lymphacytes, and accumulation of activated microglial cells and astrocytes in the virally injected striatum. In addition, the sera from the rats with intramuscular injections of AAV9-hEPO contained greater levels of antibodies against both AAV9 capsid protein and hEPO protein than the other treatment groups. hEPO gene expression was negatively correlated with the levels of circulating antibodies against AAV9 capsid protein. Intramuscular and intrastriatal re-administration of AAV9-hEPO led to increased numbers of red blood cells in peripheral blood. Our results suggest that pre-immunization with an intramuscular injection can lead to the reduction of transgene expression in the striatal re-administration.http://europepmc.org/articles/PMC3648480?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Chun Yang
Wei-Hua Yang
Sha-Sha Chen
Bao-Feng Ma
Bin Li
Tao Lu
Ting-Yu Qu
Ronald L Klein
Li-Ru Zhao
Wei-Ming Duan
spellingShingle Chun Yang
Wei-Hua Yang
Sha-Sha Chen
Bao-Feng Ma
Bin Li
Tao Lu
Ting-Yu Qu
Ronald L Klein
Li-Ru Zhao
Wei-Ming Duan
Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
PLoS ONE
author_facet Chun Yang
Wei-Hua Yang
Sha-Sha Chen
Bao-Feng Ma
Bin Li
Tao Lu
Ting-Yu Qu
Ronald L Klein
Li-Ru Zhao
Wei-Ming Duan
author_sort Chun Yang
title Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
title_short Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
title_full Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
title_fullStr Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
title_full_unstemmed Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
title_sort pre-immunization with an intramuscular injection of aav9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description We have recently demonstrated that adeno-associated virus serotype 9 (AAV9)-mediated human erythropoietin (hEPO) gene delivery into the brain protects dopaminergic (DA) neurons in the substantia nigra in a rat model of Parkinson's disease. In the present study, we examined whether pre-exposure to AAV9-hEPO vectors with an intramuscular or intrastriatal injection would reduce AAV9-mediated hEPO transduction in rat brain. We first characterized transgene expression and immune responses against AAV9-hEPO vectors in rat striatum at 4 days, 3 weeks and 6 months, and with doses ranging from 10(11) to 10(13) viral genomes. To sensitize immune system, rats received an injection of AAV9-hEPO into either the muscle or the left striatum, and then sequentially an injection of AAV9-hEPO into the right striatum 3 weeks later. We observed that transgene expression exhibited in a time course and dose dependent manner, and inflammatory and immune responses displayed in a time course manner. Intramuscular, but not intrastriatal injections of AAV9-hEPO resulted in reduced levels of hEPO transduction and increased levels of the major histocompatibility complex (MHC) class I and class II antigen expression in the striatum following AAV9-hEPO re-administration. There were infiltration of the cluster of differentiation 4 (CD4)-and CD8-lymphacytes, and accumulation of activated microglial cells and astrocytes in the virally injected striatum. In addition, the sera from the rats with intramuscular injections of AAV9-hEPO contained greater levels of antibodies against both AAV9 capsid protein and hEPO protein than the other treatment groups. hEPO gene expression was negatively correlated with the levels of circulating antibodies against AAV9 capsid protein. Intramuscular and intrastriatal re-administration of AAV9-hEPO led to increased numbers of red blood cells in peripheral blood. Our results suggest that pre-immunization with an intramuscular injection can lead to the reduction of transgene expression in the striatal re-administration.
url http://europepmc.org/articles/PMC3648480?pdf=render
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