Adenovirus expression of IL-1 and NF-kappaB inhibitors does not inhibit acute adenoviral-induced XXXX , but delays immune system-mediated elimination of transgene expression.

@entity32 @entity198 @entity7791 @entity16 @entity35 @entity20589
Despite their ability to provide long-term transgene expression in the central nervous system of na  ve hosts, the use of first-generation adenovirus (Ad) vectors for the treatment of chronic @entity16 is limited by peripheral immunization, which stimulates anti-adenovirus immune responses and causes severe @entity32 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 na  ve and preimmunized @entity35 . We assessed activation of macrophages/microglia, up-regulation of MHC I expression, infiltration of leukocytes, and transgene expression following delivery of Ads to the @entity35 striatum. After delivery of increasing doses of adenoviral vectors expressing various anti-inflammatory agents (e.g., NF-kappaB or IL-1 inhibitors) to na  ve @entity35 , no reduction in Ad-mediated CNS @entity32 was seen 1 week after delivery of Ads, compared to a control Ad.hCMV.beta-galactosidase (RAd.35) virus. We then assessed CNS @entity32 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 @entity35 receiving Ad. @entity20589 .beta-galactosidase (RAd.36)/saline or RAd.36/Ad.null (RAd.0) showed complete @entity7791 expression in the brain and levels of @entity32 comparable to those of na  ve animals. However, animals injected with RAd.36 in combination with Ads expressing NF-kappaB or IL-1 inhibitors showed a delayed @entity7791 compared to controls. As predicted, the extended presence of transgene expression was accompanied by increased levels of CNS @entity32 . 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 @entity198 , 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.
