Rapid upregulation of interferon-regulated and chemokine mRNAs upon injection of 108 international units, but not lower doses, of adenoviral vectors into the brain.
The innate immune response, characterized by the rapid induction of proinflammatory genes, plays an important role in immune responses to viral vectors utilized in gene therapy. We demonstrate that several innate proinflammatory mRNAs, i.e., those coding for the interferon (IFN)-regulated proteins interferon regulatory factor 1, 2',5'-oligoadenylate synthetase, and double-stranded-RNA-dependent protein kinase as well as those coding for the chemokines RANTES, IFN-gamma-inducible protein 10, and monocyte chemoattractant protein 1, were all increased in a statistically significant manner in response to 1 x 10(8) IU, but not lower doses, of a first-generation adenovirus injected into the naïve brain. This indicates the presence of a threshold dosage of adenovirus needed to elicit an acute innate inflammatory response.
Zirger
Jeffrey M
JM
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
Barcia
Carlos
C
Liu
Chunyan
C
Puntel
Mariana
M
Mitchell
Ngan
N
Campbell
Iain
I
Castro
Maria
M
Lowenstein
Pedro R
PR
D000256:Adenoviridae / Q000276:immunology / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000502:physiology / Q000821:virology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007267:Injections; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation
D018925:Chemokines; D012333:RNA, Messenger; D007372:Interferons