title: Adenovirus expression of IL-1 and NF-kappaB inhibitors does not inhibit acute adenoviral-induced brain inflammation, but delays immune system-mediated elimination of transgene expression.
abstract: Despite their ability to provide long-term transgene expression in the central nervous system of naïve hosts, the use of first-generation adenovirus (Ad) vectors for the treatment of chronic neurological disorders is limited by peripheral immunization, which stimulates anti-adenovirus immune responses and causes severe inflammation in the central nervous system (CNS) and elimination of transgene expression. The purpose of this study was to investigate the roles of NF-kappaB and interleukin-1 (IL-1) during inflammatory responses to Ads in the CNS of naïve and preimmunized rats. We assessed activation of macrophages/microglia, up-regulation of MHC I expression, infiltration of leukocytes, and transgene expression following delivery of Ads to the rat striatum. After delivery of increasing doses of adenoviral vectors expressing various anti-inflammatory agents (e.g., NF-kappaB or IL-1 inhibitors) to naïve rats, no reduction in Ad-mediated CNS inflammation was seen 1 week after delivery of Ads, compared to a control Ad.hCMV.beta-galactosidase (RAd.35) virus. We then assessed CNS inflammation and transgene expression at a time when control transgene expression would be completely eliminated, i.e., 1 month post-vector injection into the brain. This would optimize the assessment of an anti-inflammatory agent expressed by an adenoviral vector that could either delay or diminish immune system-mediated elimination of transgene expression. As expected, at 1 month postinfection, control preimmunized rats receiving Ad.mCMV.beta-galactosidase (RAd.36)/saline or RAd.36/Ad.null (RAd.0) showed complete elimination of beta-galactosidase expression in the brain and levels of inflammation comparable to those of naïve animals. However, animals injected with RAd.36 in combination with Ads expressing NF-kappaB or IL-1 inhibitors showed a delayed elimination of beta-galactosidase compared to controls. As predicted, the extended presence of transgene expression was accompanied by increased levels of CNS inflammation. This suggests that blocking NF-kappaB or IL-1 delays, albeit partially, transgene elimination in the presence of a preexisting systemic immune response. Prolonged transgene expression is predicted to extend concurrent brain inflammation, as noted earlier. Taken together these data demonstrate a role for NF-kappaB and IL-1 in immune system-mediated elimination of Ad-mediated CNS transgene expression.
authors.affiliation: Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Research Pavilion, Suite 5090, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stone
authors.forename: Weidong
authors.initials: W
authors.lastname: Xiong
authors.forename: Judith C
authors.initials: JC
authors.lastname: Williams
authors.forename: Anne
authors.initials: A
authors.lastname: David
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000257:Adenoviridae Infections / Q000276:immunology*; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019076:Transgenes
chemical_list: D015395:Histocompatibility Antigens Class I; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha