Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors

The innate immune response to intraportally infused adenoviral vector was e valuated in rhesus monkeys. A first-generation adenovirus-expressing lacZ ( Ad-lacZ) was administered at a dose just below that which causes severe mor bidity. The response to vector was evaluated for the initial 24 h following infusion. Clinical findings during this time were primarily limited to pet echiae, consistent with the development of thrombocytopenia and biochemical evidence of disseminated intravascular coagulation. Serum transaminases we re elevated and a lymphopenia developed. Tracking of fluorescent-labeled ve ctor demonstrated distribution to macrophages and dendritic cells of the sp leen and Kupffer cells of the liver. A systemic release of the cytokine IL- 6 occurred soon after vector infusion. Analysis of splenic cells revealed a cute activation of macrophages and dendritic cells followed by massive apop tosis. Bone marrow cultures demonstrated normal erythroid and primitive pro genitors with a significant decrease in myeloid progenitors. Similar findin gs, except the abnormality in bone marrow cultures, were observed in monkey s who received an identical dose of Ad-lacZ in which vector genes were inac tivated with psoralen and UV irradiation. These data suggest that inadverte nt targeting of antigen-presenting cells following intraportal infusion of vector leads to a systemic cytokine syndrome which may be triggered by the viral capsid proteins.