PMID- 23667683
OWN - NLM
STAT- MEDLINE
DCOM- 20131217
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 5
DP  - 2013
TI  - Pre-immunization with an intramuscular injection of AAV9-human erythropoietin 
      vectors reduces the vector-mediated transduction following re-administration in 
      rat brain.
PG  - e63876
LID - 10.1371/journal.pone.0063876 [doi]
LID - e63876
AB  - 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.
FAU - Yang, Chun
AU  - Yang C
AD  - Department of Anatomy, Capital Medical University, Beijing, China.
FAU - Yang, Wei-Hua
AU  - Yang WH
FAU - Chen, Sha-Sha
AU  - Chen SS
FAU - Ma, Bao-Feng
AU  - Ma BF
FAU - Li, Bin
AU  - Li B
FAU - Lu, Tao
AU  - Lu T
FAU - Qu, Ting-Yu
AU  - Qu TY
FAU - Klein, Ronald L
AU  - Klein RL
FAU - Zhao, Li-Ru
AU  - Zhao LR
FAU - Duan, Wei-Ming
AU  - Duan WM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130508
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 11096-26-7 (Erythropoietin)
SB  - IM
MH  - Animals
MH  - Corpus Striatum/*metabolism
MH  - Dependovirus/genetics
MH  - Erythropoietin/administration & dosage/genetics/*metabolism
MH  - Gene Transfer Techniques
MH  - Genetic Vectors/genetics/*immunology
MH  - Humans
MH  - Immunization/*methods
MH  - Injections, Intramuscular
MH  - Major Histocompatibility Complex/genetics
MH  - Neutralization Tests
MH  - Rats
MH  - Transduction, Genetic/*methods
MH  - Transgenes/genetics
PMC - PMC3648480
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/05/15 06:00
MHDA- 2013/12/18 06:00
PMCR- 2013/05/08
CRDT- 2013/05/14 06:00
PHST- 2013/02/18 00:00 [received]
PHST- 2013/04/08 00:00 [accepted]
PHST- 2013/05/14 06:00 [entrez]
PHST- 2013/05/15 06:00 [pubmed]
PHST- 2013/12/18 06:00 [medline]
PHST- 2013/05/08 00:00 [pmc-release]
AID - PONE-D-13-07489 [pii]
AID - 10.1371/journal.pone.0063876 [doi]
PST - epublish
SO  - PLoS One. 2013 May 8;8(5):e63876. doi: 10.1371/journal.pone.0063876. Print 2013.