PMID- 22929660
OWN - NLM
STAT- MEDLINE
DCOM- 20130723
LR  - 20211021
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 21
IP  - 1
DP  - 2013 Jan
TI  - Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit 
      cell-mediated immune responses.
PG  - 158-66
LID - 10.1038/mt.2012.167 [doi]
AB  - There is considerable interest in the use of adeno-associated virus serotype 9 
      (AAV9) for neurological gene therapy partly because of its ability to cross the 
      blood-brain barrier to transduce astrocytes and neurons. This raises the 
      possibility that AAV9 might also transduce antigen-presenting cells (APC) in the 
      brain and provoke an adaptive immune response. We tested this hypothesis by 
      infusing AAV9 vectors encoding foreign antigens, namely human aromatic L-amino 
      acid decarboxylase (hAADC) and green fluorescent protein (GFP), into rat brain 
      parenchyma. Over ensuing weeks, both vectors elicited a prominent inflammation in 
      transduced brain regions associated with upregulation of MHC II in glia and 
      associated lymphocytic infiltration. Transduction of either thalamus or striatum 
      with AAV9-hAADC evinced a significant loss of neurons and induction of anti-hAADC 
      antibodies. We conclude that AAV9 transduces APC in the brain and, depending on 
      the immunogenicity of the transgene, can provoke a full immune response that 
      mediates significant brain pathology. We emphasize, however, that these 
      observations do not preclude the use of AAV serotypes that can transduce APC. 
      However, it does potentially complicate preclinical toxicology studies in which 
      non-self proteins are expressed at a level sufficient to trigger cell-mediated 
      and humoral immune responses.
FAU - Ciesielska, Agnieszka
AU  - Ciesielska A
AD  - Department of Neurological Surgery, University of California San Francisco, San 
      Francisco, California 94103-0555, USA.
FAU - Hadaczek, Piotr
AU  - Hadaczek P
FAU - Mittermeyer, Gabriele
AU  - Mittermeyer G
FAU - Zhou, Shangzhen
AU  - Zhou S
FAU - Wright, J Fraser
AU  - Wright JF
FAU - Bankiewicz, Krystof S
AU  - Bankiewicz KS
FAU - Forsayeth, John
AU  - Forsayeth J
LA  - eng
GR  - R01 NS073940/NS/NINDS NIH HHS/United States
GR  - R01NS073940/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120828
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Proteins)
SB  - IM
MH  - Animals
MH  - Dependovirus/*genetics
MH  - *Genetic Vectors
MH  - *Immunity, Cellular
MH  - Proteins/*genetics/immunology
MH  - Rats
MH  - Transduction, Genetic
PMC - PMC3538301
EDAT- 2012/08/30 06:00
MHDA- 2013/07/24 06:00
PMCR- 2014/01/01
CRDT- 2012/08/30 06:00
PHST- 2012/08/30 06:00 [entrez]
PHST- 2012/08/30 06:00 [pubmed]
PHST- 2013/07/24 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - S1525-0016(16)30571-8 [pii]
AID - 10.1038/mt.2012.167 [doi]
PST - ppublish
SO  - Mol Ther. 2013 Jan;21(1):158-66. doi: 10.1038/mt.2012.167. Epub 2012 Aug 28.