Acute Toxicity

FG and multiply deleted Ads result in long-term, chronic tox-icity owing, in large part, to expression of viral genes from the vector backbone in transduced cells rendering them targets for CTLs. A plethora of studies have now convincingly demonstrated that HDAds are considerably safer than FG and multiply deleted Ads in terms of long-term, chronic toxicity due to the absence of viral coding sequences. However, in addition to chronic toxicity, systemic high-dose administration of FG and multiply deleted Ads also results in acute toxicity in mice (86), nonhuman primates (87-89), and humans (90). Schnell et al. (88) proposed that Ad-mediated acute toxicity results from activation of the innate immune response as a consequence of Ad vector uptake by antigen-presenting cells (APCs). As a consequence, these APCs are immediately activated to secrete large amounts of inflammatory cytokines. This can lead to devastating consequences, which in its most severe form is lethal systemic inflammatory response syndrome (SIRS). For nonhuman primates, systemic injection of a FGAd at >1 X 1013 vp/kg is lethal (87,89), whereas a dose of 6 X 1011 vp/kg of a multiply deleted (E1 and E4 deleted)

Ad vector was lethal in a partially OTC-deficient patient who developed SIRS and succumbed to adult respiratory distress syndrome and multiorgan failure (88,90). Ad-mediated innate immune response occurs within hours of virus administration, and is believed to be unrelated to expression of viral genes from the vector backbone, but rather triggered by the Ad cap-sid proteins. This model would imply that HDAd, like FGAd, would also elicit a potent innate immune activation following high-dose systemic delivery into humans and nonhuman primates, with possible devastating consequences. Indeed, this notion is further supported by the observation that high-dose systemic injection into nonhuman primates of an FGAd rendered transcriptionally inactive by exposure to psorlen and ultraviolet irradiation, but still able to bind and enter cells, yielded similar laboratory and clinical manifestations of innate immune activation as did biologically active FGAd (88). It is important to note that while activation of innate immunity is also observed in mice given comparable systemic doses of biologically active or inactivated FGAd, lethal SIRS does not occur and may reflect species-to-species differences in the quality of the innate immune response or sensitivities of the end organs to pathological sequelae (91). Thus, it is important to ascertain whether HDAd would also elicit an acute, innate immune response as early generation Ad vectors do in nonhuman primates, and if so, to determine whether there are any qualitative and quantitative differences in the responses. Unfortunately, the challenge of producing the large quantities of HDAd required for such experiments remains a significant obstacle that first must be addressed (see above).

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment